Use of acylaminothiazole derivatives as therapeutic agents

ABSTRACT

This invention discloses and claims a method of treatment of a disease as defined herein using a compound conforming to the general formula (I): 
                         
Wherein R 1 , R 2 , R′ 2 , R 3 , R 4  and R 5  are as described herein. Specifically, the compounds of the present invention exhibit an inhibitory effect on the production of β-amyloid peptide (β-A4) by inhibition of gamma protease. Therefore, the compounds of the present invention are useful in the treatment of pathologies such as senile dementia, Alzheimer&#39;s disease, Down&#39;s syndrome, Parkinson&#39;s disease, amyloid angiopathy and/or cerebrovascular disorders.

This application is a division of U.S. application Ser. No. 11/035,803,filed Jan. 14, 2005, now U.S. Pat. No. 7,291,636, which is acontinuation of International application No. PCT/FR2003/002,194, filedJul. 11, 2003, both of which are incorporated herein by reference intheir entirety; which claims the benefit of priority of French PatentApplication No. 02/09,061, filed Jul. 17, 2002.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to acylaminothiazole derivatives, theirpreparation and their therapeutic use.

SUMMARY OF THE INVENTION

The present invention first provides compounds conforming to the generalformula (I):

in whichR₁ represents:

-   -   a C₁₋₆ alkyl optionally substituted by one to three substituents        selected from a halogen, a hydroxyl, a trifluoromethyl, a C₁₋₆        alkoxy, a C₁₋₆ thioalkyl, a thiophene or a phenyl; or    -   a C₃₋₇ cycloalkyl, a thiophene, a benzothiophene, a pyridinyl, a        furanyl or a phenyl;    -   the phenyl groups being optionally substituted by one to three        substituents selected from a halogen atom, a C₁₋₆ alkyl, a C₁₋₆        alkoxy, a hydroxyl, a methylenedioxy, a phenoxy or a benzyloxy;        R₂ and R′₂ represent independently of one another a hydrogen        atom, a halogen atom, a hydroxyl, a C₁₋₃ alkoxy, a C₁₋₃ alkyl, a        C₃₋₇ cycloalkyl, an O—C(O)—C₁₋₁₆ alkyl group, or R₂ and R′₂        taken together form an oxo group;        R₃ represents a hydrogen atom, a C₁₋₆ alkyl optionally        substituted by a hydroxyl or a C₁₋₃ alkoxy;        R₄ and R₅ represent independently of one another:    -   a hydrogen atom, a C₁₋₇ alkyl optionally substituted by a C₃₋₇        cycloalkyl or phenyl; or    -   a C₃₋₇ cycloalkyl, a phenyl, a naphthyl or a —C(X)R₆;    -   the C₃₋₇ cycloalkyl and phenyl groups being optionally        substituted by one or more groups selected from a halogen atom,        a hydroxyl, a C₁₋₃ alkyl, a C₁₋₃ alkoxy, a trifluoromethyl, a        trifluoromethoxy, a phenyl, a phenoxy, a benzyloxy, a        —CH₂O-phenyl, an —OCH₂-pyridinyl;    -   the benzyloxy group being optionally substituted by one to three        groups selected from a halogen, a trifluoromethyl, a methyl;        on condition that at least one group R₄ or R₅ represents a group        —C(X)R₆;        X represents an oxygen atom or a sulfur atom;        R₆ represents a C₁₋₆ alkoxy group, a hydroxyl or a group —NR₇R₈;        the C₁₋₆ alkoxy group being optionally substituted by a phenyl;        R₇ and R₈ represent independently of one another:    -   a hydrogen atom, a C₁₋₆ alkyl group optionally substituted by a        C₃₋₇ cycloalkyl, a C₃₋₇ cycloalkenyl, C₁₋₃ alkoxy, a phenyl, a        morpholinyl or a pyridinyl; or    -   a C₃₋₇ cycloalkyl, C₁₋₆ alkoxy or a phenyl; or    -   R₇ and R₈, taken together with the nitrogen atom to which they        are attached, form an aziridine, azetidine, pyrrolidine,        piperidine or morpholine ring;    -   the C₃₋₇ cycloalkyl and phenyl groups being optionally        substituted by one or two substituents selected from C₁₋₃ alkyl        groups, a hydroxyl, a C₁₋₃ alkoxy or a halogen atom.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of general formula (I) a first group of preferredcompounds are those for which:

R₁ represents:

-   -   a C₁₋₅ alkyl, preferably a methyl, ethyl, 1-methylethyl,        2-methylpropyl, tert-butyl, 1-ethylpropyl, optionally        substituted by one to three substituents selected from a        fluorine, a hydroxyl, a C₁₋₄ thioalkyl, preferably a thiomethyl,        a thiophene or a phenyl; or    -   a C₄₋₇ cycloalkyl, preferably a cyclopropyl or a cyclohexyl, a        furanyl, a thiophene, a benzothiophene, a pyridinyl or a phenyl;        the phenyl being optionally substituted by one to three        substituents selected from a halogen atom, preferably a fluorine        or a chlorine, a hydroxyl, a benzyloxy or a methylenedioxy;        and/or        R₂ and R′₂ represent independently of one another a hydrogen        atom, a halogen atom, preferably a fluorine, a hydroxyl, a C₁₋₃        alkyl, preferably a methyl or an ethyl, a C₃₋₇ cycloalkyl,        preferably a cyclohexyl, a C₁₋₃ alkoxy, preferably a methoxy, an        O—C(O)—C₁₋₄ alkyl group, preferably O—C(O)—CH₃, or R₂ and R′₂        taken together form an oxo group; and/or        R₃ represents a C₁₋₄ alkyl, preferably a methyl, an ethyl, a        propyl or a butyl, optionally substituted by a C₁₋₃ alkoxy,        preferably a methoxy; and/or        R₄ and R₅ represent independently of one another:    -   a hydrogen atom, a C₁₋₇ alkyl, preferably a methyl, ethyl,        1-methylethyl, n-propyl, butyl, 2-methylpropyl, tert-butyl,        3-methylbutyl, 1-ethylpropyl, 2,2-dimethylpropyl, hexyl,        5-methylhexyl, optionally substituted by a phenyl or a C₃₋₇        cycloalkyl, preferably a cyclohexyl; or    -   a C₃₋₇ cycloalkyl, preferably a cyclopropyl or a cyclohexyl, a        phenyl, a naphthyl or a —C(X)R₆; the phenyl being optionally        substituted by one or two groups selected from a halogen,        preferably a bromine, a C₁₋₃ alkyl, preferably a methyl or a        1-methylethyl, a hydroxyl, a C₁₋₃ alkoxy, preferably a methoxy        or ethoxy, a trifluoromethyl, a trifluoromethoxy, a phenyl, a        phenoxy, a benzyloxy, a —CH₂O-phenyl, an —OCH₂-pyridinyl;    -   the benzyloxy group being optionally substituted by a group        selected from a halogen, preferably a chlorine or a fluorine, a        trifluoromethyl or a methyl;        on condition that at least one group R₄ or R₅ represents a group        —C(X)R₆; and/or        X represents an oxygen atom; and/or        R₆ represents a C₁₋₆ alkoxy group, preferably a methoxy, ethoxy,        tert-butyloxy, a hydroxyl or a group —NR₇R₈; the C₁₋₆ alkoxy        group being optionally substituted by a phenyl; and/or        R₇ and R₈ represent independently of one another:    -   a hydrogen atom, a C₁₋₃ alkyl group, preferably a methyl, ethyl        or 1-methylethyl, optionally substituted by a C₁₋₃ alkoxy,        preferably a methoxy, a C₃₋₇ cycloalkenyl, preferably a        cyclohexenyl, a phenyl, a morpholinyl or a pyridinyl; a C₁₋₃        alkoxy, preferably a methoxy; or    -   a C₃₋₆ cycloalkyl, preferably a cyclohexyl; or    -   R₇ and R₈, taken together with the nitrogen atom to which they        are attached, form an azetidine, piperidine or morpholine ring;    -   the phenyl group being optionally substituted by one or two C₁₋₃        alkoxy groups, preferably methoxy.

Among the compounds of general formula (I), a second group of preferredcompounds are those for which:

R₁ represents:

-   -   a C₁₋₆ alkyl optionally substituted by one or two substituents        selected from a hydroxyl, a C₁₋₆ alkoxy, a C₁₋₆ thioalkyl, a        trifluoromethyl, a thiophene or a phenyl; or    -   a C₃₋₇ cycloalkyl, a thiophene, a benzothiophene, a pyridinyl, a        furanyl or a phenyl;    -   the phenyl groups being optionally substituted by one to three        substituents selected from a halogen atom, a C₁₋₆ alkyl, a C₁₋₆        alkoxy, a hydroxyl, a methylenedioxy, a phenoxy or a benzyloxy;        and/or        R₂ and R′₂ represent independently of one another a hydrogen        atom, a halogen atom, a hydroxyl, a C₁₋₃ alkoxy, a C₁₋₃ alkyl, a        C₃₋₇ cycloalkyl, an O—C(O)—C₁₋₆ alkyl group, or R₂ and R′₂ taken        together form an oxo group; and/or        R₃ represents a hydrogen atom or a C₁₋₆ alkyl optionally        substituted by a hydroxyl or a C₁₋₃ alkoxy; and/or        R₄ and R₅ represent independently of one another:    -   a hydrogen atom, a C₁₋₇ alkyl optionally substituted by a C₃₋₇        cycloalkyl or phenyl; or    -   a C₃₋₇ cycloalkyl, a phenyl, a naphthyl or a —C(X)R₆;    -   the C₃₋₇ cycloalkyl and phenyl groups being optionally        substituted by one or more groups selected from a halogen atom,        a hydroxyl, a C₁₋₃ alkyl, a C₁₋₃ alkoxy, a phenyl, a phenoxy, a        benzyloxy;        on condition that at least one group R₄ or R₅ represents a group        —C(X)R₆; and/or        X represents an oxygen atom or a sulfur atom; and/or        R₆ represents a C₁₋₆ alkoxy group, a hydroxyl or a group —NR₇R₈;        and/or        R₇ and R₈ represent independently of one another:    -   a hydrogen atom, a C₁₋₆ alkyl group optionally substituted by a        C₃₋₇ cycloalkyl, a C₃₋₇ cycloalkenyl, a phenyl or a pyridinyl;        or    -   a C₃₋₇ cycloalkyl, C₁₋₆ alkoxy or a phenyl; or    -   R₇ and R₈, taken together with the nitrogen atom to which they        are attached, form an aziridine, azetidine, pyrrolidine,        piperidine or morpholine ring;    -   the C₃₋₇ cycloalkyl and phenyl groups being optionally        substituted by a C₁₋₃ alkyl group, a hydroxyl, a C₁₋₃ alkoxy or        a halogen atom.

Among the compounds of general formula (I) a third group of preferredcompounds are those for which:

R₁ represents:

-   -   a C₁₋₅ alkyl, preferably a methyl, ethyl, 1-methylethyl,        2-methylpropyl, tert-butyl, 1-ethylpropyl, optionally        substituted by one or two substituents selected from a hydroxyl,        a C₁₋₄ thioalkyl, preferably a thiomethyl, a trifluoromethyl, a        thiophene or a phenyl; or    -   a C₄₋₇ cycloalkyl, preferably a cyclopropyl or a cyclohexyl; a        furanyl, a thiophene, a benzothiophene, a pyridinyl or a phenyl;        the phenyl being optionally substituted by one or two        substituents selected from a halogen atom, preferably a fluorine        or a chlorine, a hydroxyl, a benzyloxy or a methylenedioxy;        and/or        R₂ and R′₂ represent independently of one another a hydrogen        atom, a halogen atom, preferably a fluorine, a hydroxyl, a C₁₋₃        alkyl, preferably a methyl or an ethyl, a C₃₋₇ cycloalkyl,        preferably a cyclohexyl, a C₁₋₃ alkoxy, preferably a methoxy, an        O—C(O)—C₁₋₄ alkyl group, preferably O—C(O)—CH₃, or R₂ and R′₂        taken together form an oxo group; and/or        R₃ represents a C₁₋₄ alkyl, preferably a methyl, an ethyl, a        propyl or a butyl, optionally substituted by a C₁₋₃ alkoxy,        preferably a methoxy; and/or        R₄ and R₅ represent independently of one another:    -   a hydrogen atom, a C₁₋₇ alkyl, preferably a methyl, ethyl,        1-methylethyl, n-propyl, butyl, 2-methylpropyl, tert-butyl,        3-methylbutyl, 1-ethylpropyl, 2,2-dimethylpropyl, hexyl,        5-methylhexyl, optionally substituted by a phenyl or a C₃₋₇        cycloalkyl, preferably a cyclohexyl; or    -   a C₃₋₇ cycloalkyl, preferably a cyclopropyl or a cyclohexyl; a        phenyl, a naphthyl or a —C(X)R₆;    -   the phenyl being optionally substituted by one or two groups        selected from a C₁₋₃ alkyl, preferably a 1-methylethyl, a        hydroxyl, a C₁₋₃ alkoxy, preferably a methoxy or ethoxy; a        phenoxy, a C₁₋₃ alkoxy, preferably a methoxy or an ethoxy, a        hydroxyl, a phenoxy or a benzyloxy;        on condition that at least one group R₄ or R₅ represents a group        —C(X)R₆; and/or        X represents an oxygen atom; and/or        R₆ represents a C₁₋₆ alkoxy group, preferably a methoxy, ethoxy,        tert-butyloxy, a hydroxyl or a group —NR₇R₈; and/or        R₇ and R₈ represent independently of one another:    -   a hydrogen atom, a C₁₋₃ alkyl group, preferably a methyl, ethyl        or 1-methylethyl, optionally substituted by a C₃₋₇ cycloalkenyl,        preferably a cyclohexenyl, a phenyl or a pyridinyl; or    -   a C₁₋₃ alkoxy, preferably a methoxy, a C₃₋₆ cycloalkyl,        preferably a cyclohexyl; or    -   R₇ and R₈, taken together with the nitrogen atom to which they        are attached, form an azetidine, piperidine or morpholine ring.

The compounds for which at one and the same time X, R₁, R₂, R′₂, R₃, R₄,R₅, R₆, R₇ and R₈ are as defined above in the groups of preferredcompounds are particularly preferred and more specifically, among these,the compounds for which:

R₁ represents a C₁₋₄ alkyl, preferably a 1-methylethyl or a tert-butyl,or a phenyl substituted by two fluorine atoms; and/or

R₂ represents a hydroxyl and R′₂ represents a hydrogen atom; and/or

R₃ represents a C₁₋₄ alkyl, preferably a methyl, ethyl or propyl; and/or

X represents an oxygen atom.

In the context of the present invention:

-   -   C_(t-z), where t and z may take the values from 1 to 7, is        understood to mean a carbon chain which can have from t to z        carbon atoms: for example, C₁₋₃, a carbon chain which can have        from 1 to 3 carbon atoms; C₃₋₆, a carbon chain which can have        from 3 to 6 carbon atoms; and so on;    -   alkyl is understood to mean a linear or branched saturated        aliphatic group; for example, a C₁₋₆ alkyl group represents a        linear or branched carbon chain of from 1 to 6 carbon atoms,        more particularly a methyl, ethyl, propyl, 1-methylethyl, butyl,        isobutyl, sec-butyl, tert-butyl, and so on, preferably a methyl,        ethyl, propyl or 1-methylethyl;    -   cycloalkyl is understood to mean a cyclic alkyl group; for        example, a C₃₋₇ cycloalkyl group represents a cyclical carbon        chain of from 3 to 7 carbon atoms, more particularly a        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,        preferably a cyclopentyl or cyclohexyl;    -   cycloalkenyl is understood to mean a mono- or polyunsaturated        cyclic alkyl group; for example, a C₃₋₇ cycloalkenyl group        represents a mono- or polyunsaturated cyclical carbon chain of        from 3 to 7 carbon atoms, more particularly a cyclopropenyl,        cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,        preferably a cyclopentenyl or cyclohexenyl;    -   thioalkyl is understood to mean an S-alkyl group with a linear        or branched, saturated aliphatic chain;    -   alkoxy is understood to mean an alkyloxy group with a linear or        branched, saturated aliphatic chain;    -   halogen atom is understood to mean a fluorine, a chlorine, a        bromine or an iodine; and    -   “R₂ and R′₂ taken together form an oxo group” is understood to        mean the group such that:

The compounds of general formula (I) may include one or more asymmetriccarbons. They may therefore exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers and theirmixtures, including the racemic mixtures, form part of the invention.

When the carbon bearing R₂ and R′₂ and/or the carbon bearing R₃ areasymmetric, preference is given to the compounds of general formula (I)for which the carbon bearing R₂ and R′₂ is of (S) configuration and/orthe carbon bearing R₃ is of (S) configuration.

The compounds of formula (I) may exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other useful acids, for example, for thepurification or isolation of the compounds of formula (I), also formpart of the invention.

The compounds of general formula (I) may exist in the form of hydratesor solvates, namely in the form of associations or combinations with oneor more molecules of water or with a solvent. Such hydrates and solvateslikewise form part of the invention.

The present invention secondly provides processes for preparing thecompounds of formula (I).

Thus these compounds may be prepared by processes, illustrated in thefollowing schemes, whose operating conditions are conventional for theperson skilled in the art.

A protective group is understood to mean a group which makes it possibleto block the reactivity of a functional group or position during achemical reaction which might affect it, and which liberates themolecule after cleavage according to methods known to the person skilledin the art. Examples of protective groups and of methods of protectionand deprotection are given, inter alia, in Protective groups in OrganicSynthesis, Greene et al., 2nd ed. (John Wiley & Sons, Inc., New York).

In accordance with scheme 1 the compound of formula (I) can be obtainedby peptide coupling of 2-aminothiazole of formula (III) with theacylamino acid of formula (II) according to conditions known to theperson skilled in the art, for example in the presence ofbenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) or benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) and of N-ethylmorpholine or N-methylmorpholinein an inert solvent such as dimethylformamide, acetonitrile ordichloromethane at a temperature which can range from 0° C. to theambient temperature.

The compound of formula (II) may be obtained by peptide coupling of thecompound of formula (IV) with the protected acid of formula (V), inwhich Pg represents a protective group, for example a benzyl, accordingto methods known to the person skilled in the art, as described above.The compound thus obtained is subsequently deprotected. In the casewhere the protection is a benzyl, the compound is hydrogenatedbeforehand in the presence of palladium on carbon in absolute ethanol atatmospheric pressure of hydrogen, at ambient temperature, to give thecompound of formula (II).

Alternatively the compound of formula (I) can be prepared in accordancewith scheme 2.

In accordance with this scheme the compound of formula (I) may beobtained by peptide coupling of the compound of formula (IV) with theamine of formula (VI) according to methods known to the person skilledin the art, such as for example in the presence of hydroxybenzotriazolehydrochloride (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDAC, HCl).

The compound of formula (VI) can be obtained by peptide coupling of the2-aminothiazole of formula (III) with the protected amine of formula(VII) according to methods known to the person skilled in the art, asdescribed above. The amine can be protected, for example, by means of anN-tert-butoxycarbonyl (Boc), according to conventional methods known tothe person skilled in the art, then deprotected by acidic hydrolysis, inthe presence of gaseous hydrochloric acid dissolved in an anhydroussolvent or of trifluoroacetic acid.The compounds of formula (I) in which R₂ and R′₂ form an oxo group canbe obtained by oxidizing a hydroxyl of the compound of formula (I) inwhich R₂ or R′₂ represents a hydroxyl group. The reaction can beperformed under conditions known to the person skilled in the art, forexample with the Dess-Martin reagent. These compounds can also beobtained by direct coupling of a keto acid of formula (IV) in which R₂and R′₂ together form an oxo group with an amine of formula (VI)according to conditions known to the person skilled in the art. Themethods of preparing such keto acids are known to the person skilled inthe art.

The compound of formula (III) in which R₄=—C(O)—R₆, R₆ representing aC₁₋₆ alkoxy group, can be obtained in accordance with scheme 3.

In accordance with this scheme the compound of formula (III) can beobtained by reacting an aldehyde of formula (VIII) in which R₅ is asdefined above with the methyldichloroacetate of formula (IX) in which R₆represents a C₁₋₆ alkoxy optionally substituted by a phenyl, and, forexample, sodium methoxide or ethoxide at 0° C. in an adaptation of theprocess described by Takeda (Bull. Chem. Soc. JP, 1970, vol. 43, p.2997). The mixture of products (X) and (XI) obtained is treated withthiourea in the presence, for example, of methanol or ethanol at refluxfor 4 or 8 hours to give the compound of formula (III).

The compound of formula (III) in which R₄=—C(O)—R₆, R₆ representing ahydroxyl, can be obtained by hydrolyzing the above compounds for whichR₆ represents a C₁₋₆ alkoxy group optionally substituted by a phenyl,according to conditions known to the person skilled in the art.

The compound of formula (III) in which R₅=—C(O)—R₆, R₆ representing aC₁₋₆ alkoxy group, can be obtained in accordance with scheme 4.

In accordance with scheme 4 the compound of formula (III) can beobtained by brominating a β-keto ester of formula (XIII) in which R₆represents a C₁₋₆ alkoxy optionally substituted by a phenyl, followed byreaction with the thiourea, in an adaptation of the process described byA. Barton, Breukelman, Kaye (J.C.S. Perkin I, 1982, p. 159), to give thecompound of formula (XII).

The β-keto ester of formula (XIII) can be obtained by reacting a ketoneof formula (XIV) in which R₄ is as defined above with a dialkylcarbonate of formula (XV) in which R₆ represents a C₁₋₆ alkoxyoptionally substituted by a phenyl, in an adaptation of the processdescribed by L. Crombie, R. C. F. Jones and C. J. Palmer (J.C.S. PerkinTrans. I, 1987, p. 323). The β-keto ester of formula (XIII) can also beobtained by reacting an acid of formula (XIVa) activated withcarbonyldiimidazole (CDI) with a malonate of formula (XVa) in which R₆represents a C₁₋₆ alkoxy optionally substituted by a phenyl, in anadaptation of the process described, for example, by D. W. Brooks, L.D.-L. Lu and S. Masamune (Angew. Chem. Int. Ed. Engl., 18, 1979, p. 72).

Where R₄ represents a hydrogen atom the preparation of the compound offormula (XIII) is accomplished in an adaptation of the processdescribed, for example, by Tetrahedron Letters, 42, 2001, p. 2101. Thecompound of formula (III) in which R₅=—C(O)—R₆, R₆ representing ahydroxyl, can be obtained by hydrolyzing the above compounds for whichR₆ represents a C₁₋₆ alkoxy group, according to conditions known to theperson skilled in the art.

The compound of formula (III) in which R₄ or R₅ represents a group—C(O)—NR₇R₈ can be obtained in accordance with scheme 5.

In accordance with this scheme the compound of formula (III) is obtainedby peptide coupling of the compound of formula (XVI) in which R₅ or R₄represents a carboxyl group and Pg a protective group such as a Boc witha compound of formula (XVII) in which R₇ and R₈ are as defined above inthe presence, for example, of HOBt and (EDAC, HCl). The compound thusobtained is then deprotected according to conditions known to the personskilled in the art. The compound of formula (XVI) in which Pg representsa Boc can be obtained by protecting a compound of formula (III) in whichR₄ or R₅ represents a group —C(O)R₆ and R₆ is a C₁₋₆ alkoxy optionallysubstituted by a phenyl by the action of di-tert-butyl dicarbonate inanhydrous tetrahydrofuran in the presence of dimethylaminopyridine atambient temperature, followed by hydrolysis of the carboxylate accordingto conditions known by the person skilled in the art, for example withlithium hydroxide in a 7:3 (v/v) tetrahydrofuran/water mixture at atemperature of 60° C.

The starting compounds, particularly the compounds of formula (IV), (V),(VII), (VIII), (IX), (XIV), (XIVa), (XV), (XVa) and (XVII), areavailable commercially or are described in the literature, or can beprepared by methods described therein or known to the person skilled inthe art. The compounds of formula (IV) in which R₂ or R′₂ represents ahydroxyl may be prepared by adding trimethylsilyl cyanide to an aldehydein an adaptation of the process described by D. A. Evans et al. (J.C.S.,Chem. Comm. 1973, p. 55) or by reacting sodium nitrite with analpha-amino acid in an adaptation of the process described by I. Shinnet al., (J. Org. Chem., 200, 65, p. 7667).

When a functional group of a compound is reactive, for example when R₁contains a hydroxyl, it may necessitate prior protection beforereaction. The person skilled in the art will be able to determine easilythe need for prior protection.

The meanings of R₁, R₂, R′₂, R₃, R₄, R₅, X, R₆, R₇ and R₈ in thecompounds of formula (II) to (XVII) are as defined for the compounds offormula (I).

The compounds of formula (II), (III) and (VI) are novel and likewiseform part of the invention. They are useful as synthetic intermediatesfor the preparation of compounds of general formula (I).

The following examples describe the preparation of certain compounds inaccordance with the invention. These examples are not limitative andmerely illustrate the invention.

The numbers of the compounds exemplified refer to those given in thesubsequent table. The elemental microanalyses and the NMR, IR or massspectra confirm the structures of the compounds obtained.

EXAMPLE 1 Methyl 2-amino-5-(1-methylethyl)thiazole-4-carboxylate

14.4 g of isobutyraldehyde in solution in 400 ml of diethyl ester isadmixed at 0° C. with 24.6 g of methyl dichloroacetate then dropwisewith 400 ml of a solution of sodium methoxide (0.5M) in methanol. After1 h at 0° C., 100 ml of saturated aqueous sodium chloride solution areadded and the mixture is extracted with ether. The organic phase isdried over anhydrous sodium sulfate. The ether alone is evaporated,retaining the methanol, 8 g of thiourea are added and the mixture isheated at reflux for 6 h. The reaction medium is evaporated to drynessand the residue is taken up in ethyl acetate and washed with 10% aqueousammonium hydroxide solution then with saturated aqueous sodium chloridesolution. The organic phase is dried over anhydrous sodium sulfate andthen concentrated. The residue is taken up in 100 ml of ether andfiltered on a frit to yield 18.6 g of the title compound as a whitesolid.

NMR 300 MHz (CDCl₃) δ ppm: 1.25 (d, 6H); 3.35 (s, 3H); 4.10 (m, 1H);5.50 (s, 2H).

EXAMPLE 2 Ethyl 2-amino-4-(2,2-dimethylpropyl)thiazole-5-carboxylate

4 g of 4,4-dimethylpentanone in solution in 100 ml of anhydroustetrahydrofuran are admixed with 3 g of 60% sodium hydride followed by8.2 g of diethyl carbonate, dropwise. The reaction medium is heated atreflux for 5 h.

It is cooled and hydrolyzed with 50 ml of distilled water.

The tetrahydrofuran is evaporated. The residue is extracted with ethylacetate. The organic phase is dried over sodium sulfate and thenevaporated. This gives 4.9 g of a colored oil.

NMR 300 MHz δ in ppm (CDCl₃): 1.05 (s, 9H); 1.28 (t, 3H); 2.42 (s, 2H);3.40 (s, 2H); 4.18 (q, 4H).

A suspension of 4.9 g of the β-keto ester obtained above in 75 ml ofdistilled water at 0° C. is admixed dropwise with 1.4 ml of bromine. Thereaction medium is stirred at 0° C. for 1 h then extracted with ethylacetate. The organic phase is washed with saturated sodium chloridesolution then dried over sodium sulfate.

Evaporation gives 4.1 g of an orange-colored oil.

NMR 300 MHz (CDCl₃) δ ppm: 1.00 (s, 9H); 1.30 (t, 3H); 2.60 (ms, 2H);4.25 (q, 2H); 4.75 (s, 1H).

A solution of 4.10 g of bromo-β-keto ester in 60 ml of ethanol isadmixed with 1.1 g of thiourea. The reaction medium is heated at refluxfor 6 h, then evaporated to dryness. The residue is taken up in ethylacetate and washed with 10% aqueous ammonium hydroxide solution thenwith saturated aqueous sodium chloride solution and dried over sodiumsulfate. Following evaporation, the residue is recrystallized from anethyl acetate/pentane mixture. This gives 2.1 g of a white solid.

NMR 300 MHz (CDCl₃) δ ppm: 0.97 (s, 9H); 1.21 (t, 3H); 2.92 (s, 2H);4.25 (q, 2H); 5.65 (s, 2H).

EXAMPLE 3 Methyl2-[2-[2-(3,5-difluorophenyl)acetyl-amino]propanoylamino]-5-propylthiazole-4-carboxylate(Compound 2) EXAMPLE 3.1 N-3,5-Difluorophenylacetyl-(S)-alanine

A solution of 1.72 g of 3,5-difluorophenyl-acetic acid in 50 ml ofdimethylformamide at 0° C. is admixed with 1.01 g of N-methylmorpholine,5.72 g of PyBOP, 2.15 g of (S)-alanine benzyl ester hydrochloride and1.01 g of N-methylmorpholine. The mixture is allowed to return toambient temperature and is stirred for 18 h. The reaction medium isevaporated and the residue is taken up in ethyl acetate and washed twicewith saturated aqueous sodium bicarbonate solution, a solution ofpotassium hydrogen sulfate (1M) and then with saturated aqueous sodiumchloride solution. The organic phase is dried over anhydrous sodiumsulfate. The residue is chromatographed on a silica gel column, elutingwith a 7:3 (v/v) petroleum ether/ethyl acetate mixture, to give 1.9 g ofa white solid.

NMR 300 MHz (CDCl₃) δ ppm: 1.40 (d, 3H); 3.54 (s, 2H); 4.62 (m, 1H);5.18 (m, 2H); 6.10 (d, 1H); 6.73 (t, 2H); 6.80 (d, 1H); 7.32 (m, 5H).

A solution of 1.9 g of N-3,5-difluorophenylacetyl-(S)-alanine benzylester in 80 ml of absolute ethanol is admixed with 300 mg of 10%palladium on carbon. The reaction medium is hydrogenated at atmosphericpressure and at ambient temperature for 8 h. The reaction medium isfiltered on paper, washed with absolute ethanol and then evaporated.This gives 1.37 g of a white solid.

NMR 300 MHz (CDCl₃) δ ppm: 1.36 (d, 3H); 3.48 (s, 2H); 3.70 (s, 1H);4.40 (m, 1H); 6.65 (t, 2H); 6.70 (d, 1H); 6.95 (d, 1H).

EXAMPLE 3.2 Methyl2-[2-[2-(3,5-difluorophenyl)-acetylamino]propanoylamino]-5-propylthiazole-4-carboxylate

A solution of 0.24 g of methyl 2-amino-5-propylthiazole-4-carboxylate,prepared by the process described in Example 1, in 25 ml ofdimethylformamide at 0° C. is admixed with 0.12 g of N-methylmorpholine,0.69 g of PyBOP and then 0.275 g of the compound obtained in step 3.1 ofExample 3. The reaction is allowed to return to ambient temperature andthe mixture is stirred for 18 h.

The solvent is evaporated, and the residue is taken up in ethyl acetateand washed twice with saturated aqueous sodium bicarbonate solution,once with water, once with a 1N aqueous solution of potassium hydrogensulfate and then with saturated aqueous sodium chloride solution. Theorganic phase is dried over anhydrous sodium sulfate and concentrated.The residue is chromatographed on a silica column, eluting with a 1:1(v/v) petroleum ether/ethyl acetate mixture, to give 0.22 g of a whitepowder.

LC/MS: MH⁺=426.

NMR 500 MHz (CDCl₃) δ ppm: 0.91 (q, 3H); 1.30 (d, 3H); 1.61 (m, 2H);3.06 (t, 2H); 3.53 (s, 2H); 3.77 (s, 3H); 4.38 (m, 1H); 6.98 (m, 2H);7.08 (m, 1H); 8.57 (d, 1H); 12.49 (s, 1H).

EXAMPLE 4 Methyl2-[2-[2-(3,5-difluorophenyl)acetyl-amino]propanoylamino]-4-propylthiazole-5-carboxylate(Compound 144)

A solution of 0.3 g of methyl 2-amino-4-propylthiazole-5-carboxylateprepared by the process described in Example 2, in 30 ml ofdimethylformamide at 0° C. is admixed with 0.101 g ofN-methylmorpholine, 0.86 g of PyBOP and 0.34 g ofN-3,5-difluoro-phenylacetyl-(S)—alanine, obtained in step 3.1 of Example3. The reaction medium is allowed to return to ambient temperature andthen is stirred for 18 h. After the solvent has been evaporated theresidue is taken up in ethyl acetate and washed twice with saturatedaqueous sodium bicarbonate solution, twice with water, once with a 1Maqueous solution of potassium hydrogen sulfate and then with saturatedaqueous sodium chloride solution. The organic phase is dried overanhydrous sodium sulfate and then concentrated. The residue ischromatographed on a silica column, eluting with a 3:7 (v/v) ethylacetate/petroleum ether mixture, to give 0.45 g of a white powder.

LC/MS: MH⁺=426.

NMR 500 MHz (DMSO) δ ppm: 0.88 (t, 3H); 1.32 (d, 3H); 1.66 (m, 2H); 2.95(m, 2H); 3.54 (s, 2H); 3.76 (s, 3H); 4.47 (m, 2H); 6.97 and 7.10 (2m,3H); 8.63 (d, 1H); 12.66 (s, 1H).

EXAMPLE 5 Methyl2-[2-[2-(3,5-difluorophenyl)acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 18) EXAMPLE 5.1 Methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 2.3 g of methyl2-amino-5-(1-methylethyl)thiazole-4-carboxylate, obtained in Example 1,in 100 ml of dimethylformamide at 0° C. is admixed with 1.22 g ofN-methylmorpholine, 6.34 g of PyBOP and then 2.65 g of(S)-Boc-norvaline. The reaction medium is allowed to return to ambienttemperature and then is stirred for 16 h.

Following evaporation, the residue is taken up in ethyl acetate andwashed twice with saturated aqueous sodium bicarbonate solution, twicewith water, once with a 1H aqueous solution of potassium hydrogensulfate and then with saturated aqueous sodium chloride solution. Theorganic phase is dried over anhydrous sodium sulfate and thenconcentrated. The residue is chromatographed on a silica gel column,eluting with a 3:7 (v/v) ethyl acetate/petroleum ether mixture. Thisgives 3.5 g of a white solid.

NMR 300 MHz (CDCl₃) δ ppm: 0.97 (t, 3H); 1.37 (d, 6H); 1.45 (s, 9H);1.67 (m, 2H); 1.90 (m, 2H); 3.90 (s, 3H); 4.10 (m, 1H); 4.38 (unresolvedcomplex, 1H); 4.90 (unresolved complex, 1H).

A solution of 3.3 g of the product obtained above in 60 ml oftrifluoroacetic acid is stirred at ambient temperature for 30 min,followed by evaporation. The residue is taken up in ethyl acetate andwashed twice with saturated aqueous sodium carbonate solution and thenwith saturated aqueous sodium chloride solution. The organic phase isdried over anhydrous sodium sulfate and then evaporated to give 2 g of awhite solid.

NMR 300 MHz (CDCl₃) δ ppm: 0.97 (t, 3H); 1.35 (d, 6H); 1.40 to 1.60 (m,2H); 1.80 (m, 2H); 3.60 (m, 1H); 3.97 (s, 3H); 4.12 (m, 1H).

EXAMPLE 5.2 Methyl2-[2-[2-(3,5-difluorophenyl)acetyl-amino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 0.7 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 30 ml of dimethylformamide at 0°C. is admixed with 0.255 g of N-methylmorpholine, 1.30 g of PyBOP andthen 0.43 g of 3,5-difluorophenylacetic acid. The reaction is allowed toreturn to ambient temperature and the mixture is stirred for 18 h. Thereaction medium is evaporated. The residue is taken up in ethyl acetateand washed twice with saturated aqueous sodium bicarbonate solution,twice with water, once with a 1M aqueous solution of potassium hydrogensulfate and then with saturated aqueous sodium chloride solution. Theorganic phase is dried over anhydrous sodium sulfate and thenconcentrated. The residue is chromatographed on a silica column, elutingwith a 1:1 (v/v) petroleum ether/ethyl acetate mixture, to give 0.7 g ofa white solid.

LC/MS: MH⁺=454.

NMR 500 MHz (DMSO) δ ppm: 0.85 (t, 3H); 1.26 (d, 6H); 1.28-1.65 (m, 4H);3.53 (m, 2H); 3.78 (s, 3H); 3.97 (m, 1H); 4.36 (m, 1H); 6.96 (d, 2H);7.08 (m, 1H); 8.49 (d, 1H); 12.52 (s, 1H).

EXAMPLE 6 Methyl2-[2-[2-(3,5-difluorophenyl)acetylamino]-(2S)-pentanoylamino]-4-(1-methylethyl)thiazole-5-carboxylate(Compound 146)

The procedure of Example 5 is repeated, replacing the methyl2-amino-5-(1-methylethyl)thiazole-4-carboxylate with methyl2-amino-4-(1-methylethyl)thiazole-5-carboxylate, prepared by the processdescribed in Example 2.

LC/MS: MH⁺=454.

NMR 500 MHz (DMSO) δ ppm: 0.87 (t, 3H); 1.27 (d, 6H); 1.35 (m, 2H); 1.64(m, 2H); 3.54 (s, 2H); 3.77 (s, 3H); 3.90 (m, 1H); 4.45 (m, 1H);6.96-7.09 (m, 3H); 8.53 (d, 1H); 12.69 (s, 1H).

EXAMPLE 7 Methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compounds 19 and 20)

A solution of 1 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 80 ml of dimethylformamide at 0°C. is admixed with 0.366 g of N-methylmorpholine, 1.87 g of PyBOP andthen 0.677 g of 3,5-difluoromandelic acid. The reaction medium isallowed to return to ambient temperature, stirred for 16 h and thenconcentrated. The residue is taken up in ethyl acetate and washed twicewith saturated aqueous sodium bicarbonate solution, twice with water,once with a 1M aqueous solution of potassium hydrogen sulfate and thenwith saturated aqueous sodium chloride solution. The organic phase isdried over anhydrous sodium sulfate and then concentrated.

The residue is chromatographed on a silica gel column, eluting with amixture of petroleum ether and ethyl acetate ranging from 7:3 (1:1)(v/v). The two isomers (S,S) and (R,S) can be separated in this way.This gives 0.45 g of a white powder ((S,S) isomer) and 0.50 g (mixtureof the two diastereoisomers). The mixture of the two diastereoisomers(0.50 g) is rechromatographed on a silica gel column, eluting with a 7:3(v/v) to (1:1) petroleum ether/ethyl acetate mixture, to give 0.25 g ofa white powder ((R,S) isomer).

(S,S) isomer:

LC/MS: MH⁺=470.

NMR 500 MHz (DMSO) δ ppm: 0.80 (t, 3H); 1.18 (m, 2H); 1.22 (d, 6H); 1.68(m, 2H); 3.78 (s, 3H); 3.97 (m, 1H); 4.43 (m, 1H); 5.05 (d, 1H); 6.55(d, 1H); 7.13 (m, 3H); 8.24 (d, 1H); 12.46 (s, 1H).

α_(D) ²⁰=−53° (c=1/MeOH)

(R,S) isomer:

LC/MS: MH⁺=470.

NMR 500 MHz (DMSO) δ ppm: 0.82 (t, 3H); 1.26 (d, 6H); 1.26 (m, 2H); 1.68(m, 2H); 3.78 (s, 3H); 3.97 (m, 1H); 4.40 (m, 1H); 5.07 (d, 1H); 6.42(d, 1H); 7.12 (m, 3H); 8.27 (d, 1H); 12.51 (s, 1H).

α_(D) ²⁰=−83° (c=1/MeOH)

EXAMPLE 8 Methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-(2S)-pentanoylamino]-4-(1-methylethyl)thiazole-5-carboxylate(Compounds 150 and 151)

The procedure of Example 7 is repeated, replacing the methyl2-(2-(S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate withmethyl 2-(2-(S)—pentanoylamino)-4-(1-methylethyl)thiazole-5-carboxylateobtained by the process described in step 5.1 of Example 5.

(S,S) isomer:

LC/MS: MH⁺=471.

NMR 500 MHz (DMSO) δ ppm: 0.81 (t, 3H); 1.18 (d, 6H); 1.22 (m, 2H); 1.71(m, 2H); 3.77 (s, 3H); 3.90 (m, 1H); 4.50 (m, 1H); 5.06 (s, 1H); 6.54(s, 1H); 7.12 (m, 3H); 8.30 (d, 1H); 12.66 (s, 1H).

α_(D) ²⁰=−73° (c=1/MeOH)

(R,S) isomer:

LC/MS: MH⁺=471 (95% purity)

NMR 500 MHz (DMSO) δ ppm: 0.83 (t, 3H); 1.19 (d, 6H); 1.22 (m, 2H); 1.70(m, 2H); 3.77 (s, 3H); 3.91 (m, 1H); 4.48 (m, 1H); 5.07 (s, 1H); 6.42(s, 1H); 7.12 (m, 3H); 8.34 (d, 1H); 12.67 (s, 1H).

α_(D) ²⁰=−104° (c=1/MeOH)

EXAMPLE 92-[2-[2-(3,5-Difluorophenyl)acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide(Compound 26) EXAMPLE 9.12-tert-Butoxycarbonylamino-5-(1-methylethyl)thiazole-4-carboxylic acid

A solution of 4.4 g of methyl2-amino-5-(1-methylethyl)thiazole-4-carboxylate, obtained in Example 1,in 150 ml of tetrahydrofuran is admixed with 5.27 g of di-tert-butyldicarbonate and 0.13 g of dimethylaminopyridine. The mixture is stirredat ambient temperature for 16 h. The reaction medium is evaporated. Theresidue is taken up in ethyl acetate and washed twice with a 0.5Naqueous solution of hydrochloric acid, once with water, then withsaturated aqueous sodium chloride solution. The organic phase is driedover anhydrous sodium sulfate and concentrated. This gives 6.1 g of theprotected aminothiazole derivative in the form of a solid which is usedas it is without purification.

NMR 300 MHz (CDCl₃) δ ppm: 1.25 (d, 6H); 1.50 (s, 9H); 3.85 (s, 3H);3.97 (m, 1H).

LC/MS: MH⁺=301 (M-Boc)⁺=201

A solution of 6.10 g of the product obtained above in 150 ml oftetrahydrofuran is admixed at ambient temperature with a solution of1.68 g of lithium hydroxide in 80 ml of distilled water. Thetetrahydrofuran reaction mixture is heated at reflux for 16 h and thenconcentrated. The residue is taken up in water and washed twice withethyl acetate. The aqueous phase is acidified with a 1N solution ofhydrochloric acid to approximately pH˜4, saturated with sodium chlorideand extracted twice with ethyl acetate. The organic phase is dried overanhydrous sodium sulfate and then concentrated. This gives 5.10 g of awhite solid.

LC/MS: MH⁺=287.

NMR 300 MHz (CDCl₃) δ ppm: 1.19 (d, 6H); 1.45 (s, 9H); 3.80 (s, 3H);3.90 (unresolved complex s, 1H); 4.15 (m, 1H).

EXAMPLE 9.22-tert-Butoxycarbonylamino-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide

A solution of 2 g of2-tert-butoxycarbonyl-amino-5-(1-methylethyl)thiazole-4-carboxylic acid,obtained in step 9.1, in 80 ml of dimethylformamide is admixed with 1.07g of hydroxybenzotriazole hydrate, 1.33 g of (EDAC, HCl) then 0.57 g ofN,N-dimethylamine hydrochloride and 0.77 g of N-methylmorpholine. Thereaction medium is stirred at ambient temperature for 16 h and thenconcentrated. The residue is taken up in ethyl acetate and washed twicewith saturated aqueous sodium bicarbonate solution, twice with a 1Maqueous solution of potassium hydrogen sulfate, once with water and thenwith saturated aqueous chloride solution. The organic phase is driedover anhydrous sulfate and concentrated. This gives 1.45 g of a whitesolid.

LC/MS: MH⁺=314

NMR 300 MHz (CDCl₃) δ ppm: 1.30 (d, 6H); 1.53 (s, 9H); 2.98 (s, 3H);3.09 (s, 3H); 3.40 (m, 1H); 8.00 (s, 1H).

EXAMPLE 9.3 2-Amino-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide

1.4 g of2-tert-butoxycarbonylamino-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide,obtained in step 9.2, are admixed with 30 ml of trifluoroacetic acid.The mixture is stirred at ambient temperature for 30 min and thenconcentrated. The residue is taken up in ethyl acetate and washed twicewith saturated aqueous sodium carbonate solution then with saturatedaqueous sodium chloride solution. The organic phase is dried overanhydrous sodium sulfate and then concentrated. This gives 0.90 g of awhite solid.

LC/MS: MH⁺=214

NMR 300 MHz (CDCl₃) δ ppm: 1.22 (d, 6H); 3.00 (s, 3H); 3.30 (m, 1H);4.90 (s, 1H).

EXAMPLE 9.42-((2S)-Pentanoylamino)-5-(1-methylethyl)-thiazole-4-N,N-dimethylcarboxamide

0.9 g of 2-amino-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide,obtained in step 9.3, is coupled with 1 g of (S)-Boc-norvaline by theprocess described in step 5.1 of Example 5. Chromatography on silica,eluted with a 1:1 (v/v) mixture of ethyl acetate and petroleum ether,gives 1.1 g of a viscous oil which crystallizes at ambient temperature.

LC/MS: MH⁺=413

NMR 300 MHz (CDCl₃) δ ppm: 0.97 (t, 3H); 1.30 (d, 6H); 1.40 (s, 9H);1.65 (m, 2H); 1.90 (m, 2H); 2.95 (s, 3H); 3.08 (s, 3H); 3.48 (m, 1H);4.30 (m, 1H); 5.25 (unresolved complex, 1H). 1.1 g of the compoundobtained above are deprotected in 20 ml of trifluoroacetic acid by theprocess described in step 9.3. This gives 0.77 g of a white solid.

LC/MS: MH⁺=313

NMR 300 MHz (CDCl₃) δ ppm: 0.98 (t, 3H); 1.60 (d, 6H); 1.30-1.95(unresolved complex 4H); 2.98 (s, 3H); 3.08 (s, 3H); 3.40 (m, 1H); 3.58(m, 1H).

EXAMPLE 9.52-[2-[2-(3,5-Difluorophenyl)acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide

A solution of 0.23 g of2-((2S)-pentanoyl-amino)-5-(1-methylethyl)thiazole-4-N,N-dimethyl-carboxamide,obtained in step 9.4, in 15 ml of dimethylformamide at 0° C. is admixedwith 0.088 g of N-methylmorpholine and then 0.416 g of PyBOP and 0.138 gof 3,5-difluorophenylacetic acid. The reaction medium is allowed toreturn to ambient temperature for 16 h and then is concentrated. Theresidue is taken up in ethyl acetate and washed twice with a 0.5Naqueous solution of hydrochloric acid, once with water and then withsaturated aqueous sodium chloride solution. The organic phase is driedover anhydrous sodium sulfate and concentrated. Chromatography on asilica column, eluted with a 1:1 (v/v) mixture of ethyl acetate andpetroleum ether, gives 0.26 g of a white solid.

LC/MS: MH⁺=467.

NMR 500 MHz (DMSO) δ ppm: 0.87 (t, 3H); 1.24 (d, 6H); 1.29-1.67 (m, 4H);2.86 (s, 3H); 2.95 (s, 3H); 3.22 (m, 1H); 3.54 (m, 2H); 4.41 (m, 1H);6.98 (d, 2H); 7.08 (m, 1H); 8.49 (d, 1H); 12.21 (s, 1H).

α_(D) ²⁰=−74° (c=1.0, MeOH)

EXAMPLE 102-[2-[2-(3,5-Difluorophenyl)-2-hydroxy-(2S)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide(Compound 88) and2-[2-[2-(3,5-difluorophenyl)-2-hydroxy-(2R)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide(Compound 89)

By the process described above in step 9.5 of Example 9, 0.77 g of2-((2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide,obtained in step 9.4 of Example 9, is coupled with 0.51 g of3,5-difluoromandelic acid in the presence of 0.28 g ofN-methylmorpholine and 1.4 g of PyBOP at 0° C. and chromatography on asilica column, eluted with a 75:25 (v/v) mixture of ethyl acetate andpetroleum ether, gives 0.80 g of a white solid.

LC/MS: MH⁺=483 (2 peaks: 2 diastereoisomers (R,S) and (S,S)).

NMR 500 MHz (DMSO) δ ppm: 0.72 (t, 3H); 1.06 (m, 1H); 1.16 (m, 1H); 1.27(d, 6H); 1.58 (m, 2H); 2.10 (s, 3H); 3.78 (s, 3H); 3.96 (m, 1H); 4.37(m, 1H); 5.97 (s, 1H); 7.34 and 7.47 (2m, 5H); 8.62 (s, 1H); 12.49 (s,1H).

α_(D) ²⁰=−67° (c=1.0, /MeOH)

The two diastereoisomers can be separated by preparative HPLC on a C₁₈column with an acetonitrile/H₂O gradient from 95:5 (v/v) to 5:95 in 23min.

This gives 0.1 g ((S,S) isomer) of a white solid,

LC/MS: MH⁺=483.

NMR 500 MHz (DMSO) δ ppm: 0.80 (t, 3H); 1.25 (d, 6H); 1.28 (m, 2H); 1.75(m, 2H); 2.80 (s, 3H); 3.00 (s, 3H); 3.25 (m, 1H); 4.49 (m, 1H); 5.08(s, 1H); 6.55 (broad s, 1H); 7.13 (d, 3H); 8.25 (d, 1H); 12.15 (s, 1H).

and 0.17 g ((R,S) isomer) of a white solid.

LC/MS: MH⁺=483.

NMR 500 MHz (DMSO) δ ppm: 0.88 (t, 3H); 1.22 (d, 6H); 1.30 (m, 2H); 1.68(m, 2H); 2.87 (s, 3H); 2.98 (s, 3H); 3.25 (m, 1H); 4.45 (m, 1H); 5.10(s, 1H); 6.42 (s, 1H); 7.18 (m, 5H); 8.30 (d, 1H); 12.20 (s, 1H).

EXAMPLE 11 Methyl2-[2-[2-hydroxy-2-phenyl-(2S)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)-thiazole-4-carboxylate(Compound 30) and methyl2-[2-[2-hydroxy-2-phenyl-(2R)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 31)

0.35 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in solution in 20 ml ofdimethylformamide at 0° C. is admixed with 0.13 g of N-methylmorpholine,0.67 g of PyBOP then 0.20 g of (S)-mandelic acid or (R)-mandelic acid.The reaction medium is allowed to return to ambient temperature and thenis stirred for 16 h and concentrated.

The residue is taken up in ethyl acetate and washed by the processdescribed in Example 7. Following evaporation of the organic phase, theresidue is chromatographed on a silica column, eluting with a 1:1 (v/v)ethyl acetate/petroleum ether mixture. This gives 0.36 g of the (S,S)diastereoisomer and 0.37 g of the (R,S) diastereoisomer, in the form ofa white powder.

(S,S) isomer:

LC/MS: MH⁺=434.

NMR 500 MHz (DMSO) δ ppm: 0.80 (t, 3H); 1.16 (m, 2H); 1.26 (s, 9H); 1.68(m, 2H); 3.78 (s, 3H); 3.97 (m, 1H); 4.43 (m, 1H); 4.98 (d, 1H); 6.31(d, 1H); 7.32 (m, 5H); 8.14 (d, 1H); 12.46 (s, 1H).

α_(D) ²⁰=−51° (c=1.0, /MeOH).

(R,S) isomer:

LC/MS: MH⁺=434.

NMR 500 MHz (DMSO) δ ppm: 0.85 (t, 3H); 1.28 (s, 6H); 1.28 (m, 2H); 1.68(m, 2H); 3.78 (s, 3H); 3.97 (m, 1H); 4.44 (m, 1H); 5.00 (d, 1H); 6.17(d, 1H); 7.30 (m, 5H); 8.17 (d, 1H); 12.51 (s, 1H).

α_(D) ²⁰−−110° (c=1.0, /MeOH).

EXAMPLE 12 Methyl2-[2-[2-(3,5-difluorophenyl)-2-oxoacetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)-thiazole-4-carboxylate(Compound 75)

A solution of 0.3 g of methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate,obtained in Example 7, in 40 ml of absolute dichloromethane stabilizedwith amylene is admixed with 0.55 g of Dess-Martin periodinane reagentand 0.09 g of tert-butanol. The reaction mixture is stirred at ambienttemperature for 20 h and then evaporated. The residue is chromatographed(without prior treatment) on a silica column, eluting with an 8:2 (v/v)petroleum ether/ethyl acetate mixture. This gives 0.20 g of a whitepowder.

LC/MS: MH⁺=468 (purity 100%)

NMR 500 MHz (DMSO) δ ppm: 0.97 (t, 3H); 1.20 (d, 6H); 1.40 (m, 2H); 1.80(m, 2H); 3.87 (s, 3H); 4.05 (m, 1H); 4.60 (m, 1H); 7.60 (m, 2H); 7.80(m, 1H); 7.99 (m, 2H); 9.30 (d, 1H); 12.70 (s, 1H).

EXAMPLE 13 Methyl2-[2-[-2-[-(3,5)-difluorophenyl-2-hydroxy-(2S)-acetylamino]-(2S)-pentanoylamino]-4-methylthiazole-5-carboxylate(Compound 165)

The title compound is obtained by the processes described in Examples 7and 8 as set forth below.

A solution of 0.90 g of methyl2-(2-amino-(2S)-pentanoylamino)-4-(methyl)thiazole-5-carboxylate,obtained by the process described in Example 5.1, in 75 ml ofdimethylformamide at 0° C. is admixed with 0.366 g ofN-methylmorpholine, 1.87 g of PyBOP then 0.677 g of 3,5-difluoromandelicacid. The reaction medium is allowed to return to ambient temperatureand is stirred for 16 h and then concentrated. The residue is taken upin ethyl acetate and washed twice with saturated aqueous sodiumbicarbonate solution, twice with water, once with (1M) aqueous potassiumhydrogen sulfate solution and then with saturated aqueous sodiumchloride solution. The organic phase is dried over anhydrous sodiumsulfate and then concentrated. The residue is chromatographed on acolumn of silica gel, eluting with a mixture of petroleum ether andethyl acetate ranging from 8:2 to 7:3 (v/v). This gives 0.1 g of a whitepowder (S,S isomer) and 0.7 g (mixture of the 2 diastereoisomers).

(S,S) isomer:

LC/MS: MH⁺=442

NMR 500 MHz (DMSO) δ ppm: 0.82 (t, 3H); 1.26 (m, 2H); 1.69 (m, 2H); 2.63(s, 3H); 3.77 (s, 3H); 4.50 (m, 1H); 5.07 (d, 1H); 6.55 (d, 1H); 7.16(m, 3H); 8.31 (d, 1H); 12.65 (s, 1H).

EXAMPLE 14 Methyl2-[2-[2-(3,5)-difluorophenyl)-2-oxoacetylamino]-(2S)-pentanoylamino]-4-methylthiazole-5-carboxylate(Compound 167)

A solution of 0.7 g of methyl2-[2-[2-(3,5)-difluorophenyl-2-hydroxy-(2S)-acetylamino-(25)-pentanoylamino]-4-methylthiazole-5-carboxylate,obtained in Example 13, in 80 ml of absolute dichloromethane stabilizedwith amylene is admixed with 1.35 g of Dess-Martin periodinane reagentand 0.24 g of tert-butanol. The reaction mixture is stirred at ambienttemperature for 20 h and then evaporated. The residue is chromatographed(without prior treatment) on a silica column, eluting with an 8:2 (v/v)petroleum ether/ethyl acetate mixture. This gives 0.68 g of a whitepowder.

LC/MS: MH⁺=440

α_(D) ²⁰=−87° (c=1, MeOH).

NMR 500 MHz (DMSO) δ ppm: 0.90 (t, 3H); 1.38 (m, 2H); 1.75 (m, 2H); 2.63(s, 3H); 3.78 (s, 3H); 4.61 (m, 1H); 7.69 (m, 3H); 9.43 (d, 1H).

EXAMPLE 15 Methyl2-[2-[2-hydroxy-3,3-dimethyl-(2S)-butyrylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)-thiazole-4-carboxylate(Compound 97)

A solution of 0.24 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 10 ml of dimethylformamide at 0°C. is admixed with 97 μl of N-methylmorpholine, 0.116 g of(S)-(−)-2-hydroxy-3,3-dimethylbutyric acid and then 0.46 g of PyBOP. Thereaction medium is stirred for 18 hours after return to ambienttemperature and then is concentrated under reduced pressure. The residueis taken up in 50 ml of ethyl acetate and washed successively with 50 mlof a saturated solution of KHSO₄ in H₂O, 50 ml of a saturated solutionof K₂CO₃ in H₂O, 50 ml of saturated NaCl solution and then 50 ml of H₂O.After drying and evaporation of the organic phase, the residue ischromatographed on a silica (40 g) column, eluted with a gradient from100% of petroleum ether to a 30/70 mixture of petroleum ether/ethylacetate (v/v). This gives 0.269 g of white crystals.

LC/MS: MH⁺=414.

NMR 500 MHz (DMSO) δ ppm: 0.90 (t, 3H); 0.93 (s, 9H); 1.30 (d, 6H); 1.32(m, 2H); 1.71 (m, 2H); 3.58 (d, 1H); 3.82 (s, 3H); 4.02 (m, 1H); 4.52(m, 1H); 5.60 (d, 1H); 7.82 (d, 1H); 12.45 (s, 1H).

α_(D) ²⁰=−74° (c=1.0, /MeOH).

EXAMPLE 16 Methyl2-[2-(2-fluoro-2-phenyl-(2S)-acetylamino-(2S)-pentanoylamino]-5(1-methylethyl)thiazole-4-carboxylate(Compound 98) and methyl2-[2-(2-fluoro-2-phenyl-(2R)-acetylamino-(2S)-pentanoylamino]-5(1-methylethyl)thiazole-4-carboxylate(Compound 99)

A solution of 0.60 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 15 ml of dimethylformamide at 0°C. is admixed with 242 μl of N-methylmorpholine, 0.34 g ofα-fluorophenylacetic acid and then 1.144 g of PyBOP. The reaction mediumis stirred for 18 hours following return to ambient temperature and thenis concentrated under reduced pressure. The residue is taken up in 50 mlof ethyl acetate and washed successively with 50 ml of a saturatedsolution of KHSO₄ in H₂O, 50 ml of a saturated solution of K₂CO₃ in H₂O,50 ml of saturated NaCl solution and then 50 ml of H₂O. After drying andevaporation of the organic phase, the residue is chromatographed on asilica (40 g) column, eluted with a gradient from 100% petroleum etherto a 30/70 mixture of petroleum ether/ethyl acetate (v/v). This gives123 mg of (S,S) isomer and 177 g of (R,S) isomer.

(S,S) isomer:

LC/MS: MH⁺=436.

NMR 500 MHz (DMSO) δ ppm: 0.87 (t, 3H); 1.22 (d, 6H); 1.32 (m, 2H); 1.70(m, 2H); 3.78 (s, 3H); 3.98 (m, 1H); 4.52 (m, 1H); 5.90 and 6.00 (2s,1H); 7.44 (m, 5H); 8.70 (d, 1H); 12.55 (s, 1H).

α_(D) ²⁰=−55° (c=1.0, /MeOH).

(R,S) isomer:

LC/MS: MH⁺=436.

NMR 500 MHz (DMSO) δ ppm: 0.90 (t, 3H); 1.24 (m, 2H); 1.30 (s, 6H); 1.77(m, 2H); 3.85 (s, 3H); 4.05 (m, 1H); 4.48 (m, 1H); 5.97 and 6.05 (2s,1H); 7.50 (m, 5H); 8.80 (d, 1H); 12.62 (s, 1H).

α_(D) ²⁰=−71.3° (c=1.0, MeOH).

EXAMPLE 17 Methyl2-[2-[2-(3-chloro)-2-hydroxy-(2S)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)-thiazole-4-carboxylate(Compound 107) EXAMPLE 17.1 2-(3-Chlorophenyl)-2-hydroxy-(2S)-aceticacid

A solution of 2.85 ml of 3-chlorobenzaldehyde in 20 ml ofdichloromethane is admixed cautiously with 3.66 ml of trimethylsilylcyanide and then with a catalytic amount of zinc iodide (ZnI₂). Thereaction medium is stirred for 3 hours at ambient temperature and thenat 60° C. for 2 hours. The reaction medium is cooled to 0° C. and 9 mlof concentrated HCl are added. The reaction medium is stirred for 18hours at ambient temperature and then 1 hour at reflux. After cooling,the reaction mixture is poured into water and extracted twice with 50 mlof AcOEt. The combined organic phases are extracted with 100 ml of 7.5NNaOH at 4° C. After separation, the aqueous phase is washed with 3×50 mlof AcOEt. The aqueous phase is acidified with 70 ml of 12N HCl andextracted with 3×50 ml of AcOEt. The combined organic phases are driedand the solvent is evaporated.

(R)-3-Chloromandelic acid is separated by crystallization in the form of(R)-(+)-phenylethylamine salt. (S)-3-Chloromandelic acid is obtainedfrom the mother liquor by crystallization in the form of(S)-(−)-phenethylamine salt. This gives 78 mg of white crystals.

The acid obtained is used without further purification in the followingstep.

EXAMPLE 17.2 Methyl2-[2-[2-(3-chloro)-2-hydroxy-(2S)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)-thiazole-4-carboxylate

A solution of 0.072 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 5 ml of dimethylformamide at 0° C.is admixed with 29-μl of N-methylmorpholine, 0.081 g of(S)-3-chloromandelic acid and then 0.137 g of PyBOP. The reaction mediumis stirred for 40 hours after return to ambient temperature and then isconcentrated under reduced pressure. The residue is taken up in 50 ml ofethyl acetate and washed successively with 50 ml of a saturated solutionof KHSO₄ in H₂O, 50 ml of a saturated solution of K₃CO₃ in H₂O, 50 ml ofsaturated NaCl solution and then 50 ml of H₂O. After drying andevaporation of the organic phase, the residue is chromatographed on asilica (40 g) column, eluted with a gradient from 100% of petroleumether to 100% of ethyl acetate. This gives 0.059 g of white crystals.

LC/MS: MH⁺=468.

NMR 500 MHz (DMSO) δ ppm: 0.87 (t, 3H); 1.20 (m, 2H); 1.22 (d, 6H); 1.70(m, 2H); 3.80 (s, 3H); 4.00 (m, 1H); 4.43 (m, 1H); 5.02 (s, 1H); 6.44(s, 1H); 7.30 (m, 3H); 7.45 (s, 1H); 8.20 (d, 1H); 12.45 (s, 1H).

EXAMPLE 18 Methyl2-[2-(3-ethyl-2-hydroxy-(2S)-pentanoylamino)-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 108) and methyl2-[2-(3-ethyl-2-hydroxy-(2R)-pentanoylamino)-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 109) EXAMPLE 18.1 3-Ethyl-2-hydroxypentanoic acid

A solution of 1.24 ml of 2-ethylbutyraldehyde in 18 ml of anhydrousdichloromethane is admixed cautiously with 1.5 ml of trimethylsilylcyanide and then with a catalytic amount of ZnI₂. The reaction medium isstirred for 2 hours at ambient temperature and then at 60° C. for 3.5hours. The reaction medium is cooled to 0° C. and 3.5 ml of concentratedHCl are added. The reaction medium is stirred for 18 hours at ambienttemperature and then for 1 hour at reflux. After cooling, the reactionmixture is poured into water and extracted twice with 50 ml of AcOEt.The combined organic phases are extracted with 100 ml of 7.5N NaOH at 4°C. After separation, the aqueous phase is washed with 3×50 ml of AcOEt.The aqueous phase is acidified with 70 ml of 12N HCl and extracted with3×50 ml of AcOEt. The combined organic phases are dried and the solventis evaporated.

The acid obtained is used without further purification in the followingstep.

EXAMPLE 18.2 Methyl2-[2-(3-ethyl-2-hydroxy-(2S)-pentanoylamino)-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylateand methyl2-[2-(3-ethyl-2-hydroxy-(2R)-pentanoylamino)-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 0.457 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylateobtained in step 5.1 of Example 5, in 15 ml of dimethylformamide at 0°C. is admixed with 181 μl of N-methylmorpholine, 0.45 g of3-ethyl-2-(S)-hydroxypentanoic acid and then 0.858 g of PyBOP. Thereaction medium is stirred for 18 hours after return to ambienttemperature and then is concentrated under reduced pressure. The residueis taken up in 50 ml of ethyl acetate and washed successively with 50 mlof a saturated solution of KHSO₄ in H₂O, 50 ml of a saturated solutionof K₂CO₃ in H₂O, 50 ml of saturated NaCl solution and then 50 ml of H₂O.After drying and evaporation of the organic phase, the residue ischromatographed on a silica (40 g) column, eluted with a gradient from100% of petroleum ether to a 20/80 mixture of petroleum ether/ethylacetate (v/v). This gives 78 mg of (S,S) isomer and 131 mg of (R,S)isomer.

(S,S) isomer:

LC/MS: MH⁺=428.

NMR 500 MHz (DMSO) δ ppm: 0.86 (t, 3H); 0.93 (m, 6H); 1.24 (m, 2H); 1.32(d, 6H); 1.38 (m, 4H); 1.55 (m, 1H); 1.72 (m, 2H); 3.78 (s, 3H); 3.98(m, 1H); 4.05 (m, 1H); 4.55 (m, 1H); 5.55 (d, 1H); 7.92 (d, 1H); 12.50(s, 1H).

α_(D) ²⁰=53.9° (c=1.0, /MeOH).

(R,S) isomer:

LC/MS: MH⁺=436.

NMR 500 MHz (DMSO) δ ppm: 0.80 (t, 3H); 0.90 (m, 6H); 1.20 (m, 2H); 1.30(d, 6H); 1.34 (m, 4H); 1.55 (m, 1H); 1.74 (m, 2H); 3.86 (s, 3H); 4.00(m, 2H); 4.53 (m, 1H); 5.42 (d, 1H); 8.00 (d, 1H); 12.54 (s, 1H).

α_(D) ²⁰=26.9° (c=1.0, /MeOH).

EXAMPLE 19 Methyl2-[2-[3-(3,5-difluorophenyl)-2-hydroxy-(2S)-propionylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 110) EXAMPLE 19.13-(3,5-Difluorophenyl)-2-hydroxy-(2S)-propionic acid

A suspension of 1.6 g of (S)-3,5-difluoro-phenyalanine in 5.3 ml ofH₂SO₄ (2.5N) is admixed dropwise at 0° C. with a solution of 0.829 g ofsodium nitrite in 4.2 ml of H₂O. The reaction mixture is stirred for 2hours at 0° C. and then for 17 hours at ambient temperature. Thereaction mixture is extracted with 2×100 ml of AcOEt. The combinedorganic phases are washed with 100 ml of saturated NaCl solution in H₂O.Drying gives 1.197 g of yellow crystals. The acid obtained is usedwithout further purification in the following step.

EXAMPLE 19.2 Methyl2-[2-[3-(3,5-difluorophenyl)-2-hydroxy-(2S)-propionylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 0.897 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 10 ml of dimethylformamide at 0°C. is admixed with 363 μl of N-methylmorpholine, 0.666 g of3-(3,5-difluorophenyl)-2-hydroxypropionic acid and then 1.72 g of PyBOP.The reaction medium is stirred for 17 hours after return to ambienttemperature and then is concentrated under reduced pressure. The residueis taken up in 50 ml of ethyl acetate and washed successively with 50 mlof a saturated solution of KHSO₄ in H₂O, 50 ml of a saturated solutionof K₂CO₃ in H₂O, 50 ml of a saturated solution of NaCl and then 50 ml ofH₂O. After drying and evaporation of the organic phase, the residue ischromatographed on a silica (90 g) column, eluted with a gradient from100% of petroleum ether to a 10/90 mixture of petroleum ether/ethylacetate (v/v). This gives 0.43 g of white crystals.

LC/MS: MH⁺=484.

NMR 500 MHz (DMSO) δ ppm: 0.82 (m, 3H); 1.10 (m, 2H); 1.27 (m, 6H); 1.61(m, 2H); 2.83 and 2.95 (2m, 1H); 3.77 (s, 3H); 3.96 (m, 1H); 4.21 (m,1H); 4.43 (m, 1H); 5.68 and 5.81 (2d, 1H); 6.93-7.01 (m, 3H); 7.84 and7.97 (2d, 1H); 12.46 (s, 1H).

α_(D) ²⁰=−32.8° (c=1.0, /MeOH).

EXAMPLE 20 Methyl2-[2-[2-(2-benzyloxyphenyl)-2-hydroxyacetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 122) EXAMPLE 20.1 (2-Benzyloxyphenyl)hydroxyacetic acid

A solution of 1.24 ml of 2-benzyloxy-benzaldehyde in 10 ml of anhydrousdichloromethane is admixed cautiously with 4.4 ml of trimethylsilylcyanide and then with a catalytic amount of ZnI₂. The reaction medium isstirred for 2.5 hours at ambient temperature and then at 60° C. for 4hours. The reaction medium is cooled to 0° C. and 10.5 ml ofconcentrated HCl are added. The reaction medium is stirred for 18 hoursat ambient temperature and then for 1 hour at reflux. After cooling, thereaction mixture is poured into water and extracted twice with 50 ml ofAcOEt. The combined organic phases are extracted with 100 ml of 7.5NNaOH at 4° C. After separation, the aqueous phase is washed with 3×50 mlof AcOEt. The aqueous phase is acidified with 70 ml of 12N HCl andextracted with 3×50 ml of AcOEt. The combined organic phases are driedand the solvent is evaporated. The acid obtained is used without furtherpurification in the following step.

EXAMPLE 20.2 Methyl2-[2-[2-(2-benzyloxyphenyl)-2-hydroxyacetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 1.88 g of methyl2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 5.1 of Example 5, in 50 ml of dimethylformamide at 0°C. is admixed with 760 μl of N-methylmorpholine, 13 g of(2-benzyloxyphenyl)hydroxy-acetic acid and then 3.6 g of PyBOP. Thereaction mixture is stirred for 17 hours after return to ambienttemperature and then is concentrated under reduced pressure. The residueis taken up in 100 ml of ethyl acetate and washed successively with 100ml of a saturated solution of KHSO₄ in H₂O, 100 ml of a saturatedsolution of K₂CO₃ in H₂O, 100 ml of saturated NaCl solution and then 100ml of H₂O. After drying and evaporation of the organic phase, theresidue is chromatographed on a silica (90 g) column, eluted with agradient from 100% petroleum ether to a 30/70 mixture of petroleumether/ethyl acetate (v/v). This gives 0.43 g of a white foam.

LC/MS: MH⁺=540.

α_(D) ²⁰=87.0° (c=1.0, /MeOH).

NMR 500 MHz (DMSO) δ ppm: 0.85 (m, 3H); 1.26 (m, 2H); 1.28 (d, 6H); 1.69(m, 2H); 3.78 (s, 3H); 3.98 (m, 1H); 4.47 (m, 1H); 5.22 (s, 2H); 5.33(2d, 1H); 6.07 and 6.11 (2d, 1H); 6.90-7.50 (m, 8H) 8.00 (m, 1H); 12.48(s, 1H).

EXAMPLE 21 Methyl2-[2-[2-hydroxy-2-(2-hydroxyphenyl)-acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)-thiazole-4-carboxylate(Compound 128)

A solution of 1.187 g of methyl2-[2-[2-(2-benzyloxyphenyl)-2-hydroxyacetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate,obtained in Example 20, in 10 ml of ethanol under a nitrogen atmosphereis admixed with 144 mg of Pd/C (10%). The reaction mixture is stirredfor 24 h under an H₂ atmosphere. The catalyst is removed by filtrationand the solvent is evaporated under reduced pressure. The residue ischromatographed on a silica (90 g) column, eluted with a gradient from100% of petroleum ether to a 40/60 mixture of petroleum ether/ethylacetate (v/v). This gives 0.68 g of white crystals.

LC/MS: MH⁺=450.

α_(D) ²⁰=−89.5° (c=1.0, /MeOH).

NMR 500 MHz (DMSO) δ ppm: 0.91 (m, 3H); 1.28 (m, 2H); 1.30 (d, 6H); 1.80(m, 2H); 3.85 (s, 3H); 4.07 (m, 1H); 4.53 (m, 1H); 5.31 and 5.35 (2s,1H); 6.87 (m, 2H); 7.13 (m, 1H); 7.27 (m, 1H); 8.17 (m, 1H); 9.66 (broads, 1H); 12.49 (s, 1H).

EXAMPLE 22 Methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxy-(2S)-acetylamino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 60) and methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxy-(2R)-acetylamino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 61) EXAMPLE 22.1 Methyl2-[(2S)-2-amino-3-methoxypropionylamino]-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 2.00 g of methyl2-amino-5-(1-methylethyl)thiazole-4-carboxylate, obtained in Example 1,in 100 ml of dimethylformamide at 0° C. is admixed with 1.01 g ofN-methylmorpholine, 5.72 g of PyBOP and then 2.40 g of(S)—BOC—O-methylserine, dicyclohexylamine. The reaction is allowed toreturn to ambient temperature and the mixture is stirred for 18 h.

The solvent is evaporated and the residue is taken up in ethyl acetateand washed twice with saturated aqueous sodium bicarbonate solution,once with water and once with a 1N aqueous solution of potassiumhydrogen sulfate and then with saturated aqueous sodium chloridesolution.

The organic phase is dried over anhydrous sodium sulfate andconcentrated. The residue is chromatographed on a silica column, elutingwith an 8:2 (v/v) petroleum ether/ethyl acetate mixture, to give 2.70 gof a white powder.

LC/MS: MH⁺=402.

NMR 300 MHz (CDCl₃): 1.33 (d, 6H); 1.48 (s, 9H); 3.32 (s, 3H); 3.33 and3.99 (2m, 2H); 3.55 (m, 1H); 3.92 (s, 3H); 4.13 (m, 1H); 4.5 (broad s1H); 5.40 (d, 1H).

A solution of 4.30 g of the product obtained in the manner describedabove, in 60 ml of trifluoroacetic acid, is stirred at ambienttemperature for 30 min, and then the solution is evaporated.

The residue is taken up in ethyl acetate and washed twice with saturatedaqueous sodium carbonate solution and then with saturated aqueous sodiumchloride solution. The organic phase is dried over anhydrous sodiumsulfate and then evaporated to give 0.50 g of a white solid, which isused without purification in the following step.

EXAMPLE 22.2 Methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxy-(2S)-acetylamino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylateand methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxy-(2R)-acetylamino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate

A solution of 0.29 g of methyl2-[(2S)-2-amino-3-methoxypropionylamino]-5-(1-methylethyl)thiazole-4-carboxylate,obtained in step 22.2, in 80 ml of dimethylformamide at 0° C. is admixedwith 0.106 g of N-methylmorpholine, 0.55 g of PyBOP and then 0.20 g of3,5-difluoromandelic acid. The reaction medium is allowed to return toambient temperature and is stirred for 16 h and then concentrated. Theresidue is taken up in ethyl acetate and washed twice with saturatedaqueous sodium bicarbonate solution, twice with water, once with a 1Maqueous solution of potassium hydrogen sulfate and then with saturatedaqueous sodium chloride solution. The organic phase is dried overanhydrous sodium sulfate and then concentrated. The residue ischromatographed on a column of silica gel, eluting with a (1:1) (v/v)petroleum ether/ethyl acetate mixture. The two isomers (S,S) and (R,S)can be separated in this way. This gives 0.10 g of a white powder [(S,S)isomer] and 0.50 g [(R,S) isomer].

(S,S) isomer:

LC/MS: MH⁺=472.

NMR 500 MHz (DMSO) δ ppm: 1.25 (d, 6H); 3.23 (s, 2H); 3.59 (m, 1H); 3.61(m, 1H); 3.78 (s, 3H); 3.96 (m, 1H); 4.64 (m, 1H); 5.09 (s, 1H); 6.62(s, 1H); 7.13 (m, 3H); 8.23 (d, 1H); 12.53 (s, 1H).

(R,S) isomer:

LC/MS: MH⁺=472.

NMR 500 MHz (DMSO) δ ppm: 1.26 (t, 3H); 3.23 (s, 2H); 3.62 (m, 1H); 3.71(m, 1H); 3.78 (s, 3H); 3.97 (m, 1H); 4.00 (m, 1H); 5.10 (s, 1H); 6.56(s, 1H); 7.13 (m, 3H); 8.26 (d, 1H); 12.59 (s, 1H).

EXAMPLE 23 Methyl2-[2-[2-(3,5-difluorophenyl)acetyl-amino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 59)

A solution of 0.21 g of methyl2-[2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate,obtained in Example 22, in 30 ml of dimethylformamide at 0° C. isadmixed with 0.09 g of N-methylmorpholine, 0.42 g of PyBOP and then 0.14g of 3,5-difluorophenylacetic acid.

The reaction is allowed to return to ambient temperature and the mixtureis stirred for 18 h. The reaction medium is evaporated. The residue istaken up in ethyl acetate and washed twice with saturated aqueous sodiumbicarbonate solution, twice with water, once with 1M aqueous solution ofpotassium hydrogen sulfate and then with saturated aqueous sodiumchloride solution. The organic phase is dried over anhydrous sodiumsulfate and then concentrated. The residue is chromatographed on asilica column, eluting with a 1:1 (v/v) petroleum ether/ethyl acetatemixture to give 0.12 g of a white solid.

LC/MS: MH⁺=456.

NMR 500 MHz (DMSO) δ ppm: 1.26 (t, 3H); 3.28 (d, 3H); 3.55 (s, 2H); 3.57(m, 2H); 3.78 (s, 3H); 3.97 (m, 1H); 4.64 (m, 1H); 6.98 (d, 2H); 7.08(m, 1H); 8.57 (d, 1H); 12.54 (s, 1H).

EXAMPLE 24 Methyl2-[2-[2-(3,5-difluorophenyl)acetylamino]-(2S)-butyrylamino]-5-(1-methylethyl)thiazole-4-carboxylate(Compound 51) EXAMPLE 24.1 Methyl2-[(2S)-2-aminobutyrylamino]-5-(1-methylethyl)thiazole-4-carboxylate

2.03 g of 2-(2S)-(tert-butoxycarbonyl)amino-butyric acid in 50 ml ofN,N-dimethylformamide are coupled with 1.92 g of methyl2-amino-5-(1-methylethyl)thiazole-4-carboxylate, obtained in Example 1,with 5.72 g of PyBOP and 1.07 g of N-methylmorpholine to give, afterchromatography, 2.50 g of a white powder. Deprotection of the BOC groupin TFA gives, after basic washing, 1.60 g of a white solid, which isused without purification in the following step:

LC/MS: MH⁺=286.

EXAMPLE 24.2 Methyl2-[2-[2-(3,5-difluorophenyl)acetylamino]-(2S)-butyrylamino]-5-(1-methylethyl)thiazole-4-carboxylate

Methyl2-[(2S)-2-aminobutyrylamino]-5-(1-methylethyl)thiazole-4-carboxylate(1.6 g), obtained in step 24.1, in N,N-dimethylformamide is coupled bythe process described in Example 5.2 with 0.38 g of3,5-difluorophenylacetic acid, 1.14 g of PyBOP and 0.22 g ofN-methylmorpholine to give, after chromatography, 0.66 g of a whitepowder.

LC/MS: MH⁺=440.

NMR 500 MHz (DMSO) δ ppm: 0.79 (t, 3H); 1.26 (d, 6H); 1.73 (m, 2H); 3.78(s, 3H); 3.96 (m, 1H); 4.36 (m, 1H); 5.06 (s, 1H); 6.56 (s, 1H); 7.13(m, 3H); 8.22 (d, 1H); 12.46 (s, 1H).

α_(D) ²⁰=−73° (c=1.0, /MeOH).

EXAMPLE 252-[2-[2-(3,5-Difluorophenyl)acetylamino]-(2S)-pentanoylamino]-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide(Compound 176)

The title compound is obtained using the process described in Example 9as further set forth below.

EXAMPLE 25.12-Amino-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide

A solution of 5.58 g of methyl 2-amino-4-methylthiazole-5-carboxylate,obtained by the process described in Example 2, in tetrahydrofuran isreacted with 7.19 g of di-tert-butyl dicarbonate and 0.18 g ofdimethylaminopyridine to give 6.90 g of a white powder, which is used asit is without purification.

LC/MS: MH⁺=187.

NMR 300 MHz (CDCl₃): 1.45 (s, 9H); 2.48 (s, 3H); 9.80 (broad s, 1H).

2-Amino-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide, protectedon the amine by a BOC, is obtained by coupling the process described inExample 9.2. This is done by employing a solution of 1.50 g of ethyl2-tert-butoxycarbonylamino-4-methylthiazole-5-carboxylate in 100 ml ofN,N-dimethylformamide with 0.88 g of hydroxybenzotriazole hydrate, 0.95g of EDAC, HCl and 0.78 g of N-methyl-N-phenethylamine. Chromatographygives 1.10 g of a white powder.

LC/MS: MH⁺=376.

(M-BOC)⁺=276.

The BOC protective group is deprotected by the process described inExample 9.3. This gives 0.90 g of2-amino-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide in the formof a white powder.

LC/MS: MH⁺=276.

EXAMPLE 25.22-(2-Amino-(2S)-pentanoylamino)-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide

0.90 g of 2-amino-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide,obtained in step 25.1, is coupled with 0.78 g of (S)—BOC-norvaline bythe process described in step 5.1 of Example 5. Chromatography onsilica, eluted with a 1:1 (v/v) ethyl acetate/petroleum ether mixture,gives 1.05 g of a white foam.

LC/MS: MH⁺=475.

1.05 g of the compound obtained above are deprotected in 25 ml oftrifluoroacetic acid by the process described in step 9.3. This gives0.80 g of a white solid.

LC/MS: MH⁺=375.

EXAMPLE 25.32-[2-[2-(3,5-Difluorophenyl)acetylamino]-(2S)-pentanoylamino]-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamide

The same process is followed as in Example 5.2.

0.80 g of2-(2-amino-(2S)-pentanoylamino)-4-methylthiazole-5-N-methyl-N-phenylethylcarboxamidein 50 ml of N,N-dimethylformamide is coupled with 1.19 g of PyBOP, 0.23g of N-methylmorpholine and 0.40 g of 3,5-difluorophenylacetic acid togive, after purification on a column of silica gel, eluted with a 1:1(v/v) ethyl acetate/petroleum ether mixture, 0.67 g of a white powder.

LC/MS: MH⁺=259.

NMR 500 MHz (DMSO) δ ppm: 0.92 (t, 3H); 1.38 (m, 2H); 1.65 (m, 2H); 2.14(s, 3H); 2.88 (m, 2H); 2.97 (s, 3H); 3.63 (s, 2H); 3.67 (m, 2H); 4.51(m, 1H); 7.04 (d, 2H); 7.12 (t, 1H); 7.24-7.30 (m, 5H); 8.55 (d, 1H);12.46 (s, 1H).

α_(D) ²⁰=−103° (c=1, MeOH).

The table which follows illustrates the chemical structures and physicalproperties of some examples of compounds according to the invention.

TABLE (I)

alpha D NMR(DMSO d6 unless specified) (C = 1, * signifies 300 MHz . **signifies 360 MHz - Cpd. R₁ R₂, R′₂ R₃ R₄ R₅ R₆ R₇, R₈ MeOH) ***signifies 500 MHz 1. 3,5- difluorophenyl H, H —CH₃ —COR₆ —CH(CH₃)₂ OCH₃— — 1.16 (d,6H), 1.25 (d,3H), 3.53 (s,2H), 3.77 (s,3H), 3.97 (m,1H),4.36 (m,1H), 6.97 (d,9H), 7.10 (m,1H), 8.55 (d,1H), 12.47 (s,1H)** 2.3,5- difluorophenyl H, H —CH₃ —COR₆ —CH(CH₃)₂CH₃ OCH₃ — — 0.91 (q,3H),1.30(d,3H), 1.61 (m,2H), 3.06 (t,2H), 3.53 (s,2H), 3.77 (s,3H), 4.38(m,1H), 6.98 (m,2H), 7.08 (m,1H), 8.57 (d,1H), 12.49 (s,1H)*** 3. 3,5-difluorophenyl H, H —CH₃ —COR₆ —CH₂CH(CH₃)₂ OCH₃ — — 0.89 (d,6H), 1.30(d,3H), 1.85 (m,1H), 2.98 (d,2H), 3.53 (s,2H), 3.77 (s,3H), 4.38 (m,1H),6.98 (d,2H), 7.09 (m,1H), 8.57 (d,1H), 12.50 (s,1H)** 4. 3,5-difluorophenyl H, H —CH₃ —COR₆ —CH₂C(CH₃)₃ OCH₃ — — 0.91 (s,9H), 1.31(d,3H), 3.07 (s,2H), 3.53 (s,2H), 3.76 (s,3H), 4.38 (m,1H), 6.97 (d,2H),7.08 (m,1H), 8.57 (d,1H), 12.51 (s,1H)** 5. 3,5- difluorophenyl H, H—CH₃ —COR₆

OCH₃ — — 1.30 (d,3H), 1.31 (m,5H), 1.67-1.97 (m,5H), 3.53 (s,2H), 3.65(m,1H), 3.77 (s,3H), 4.38 (m,1H), 6.98 (d,2H), 7.08 (m,1H), 9.67 (d,1H),12.47 (s,1H)** 6. 3,5- difluorophenyl H, H —CH₃ —COR₆ —(CH₂)₅CH₃ OCH₃ —— 0.85 (t,3H), 1.29 (9H), 1.56 (m,2H), 3.10 (t,2H), 3.69 (t,2H), 3.77(s,3H), 4.41 (m,1H), 6.97 (m,2H) 7.07 (m,1H), 8.56 (d,1H), 12.48(s,1H)** 7. 3,4- difluorophenyl H, H —CH₃ —COR₆ phenyl OCH₃ — — 1.33(d,3H), 3.50 (s,2H), 3.67 (s,3H), 4.42 (m,l H), 7,28-7.48 (m,3H), 8.57(d,1H), 12.70 (s,1H)** 8. 3,4- difluorophenyl H, H —CH₃ —COR₆

OCH₃ — — 1.25 (d,3H), 3.48 (s,2H), 3.85 (s,3H), 4.35 (m,1H), 4.47(s,2H), 7.20-7.40 (m,3H), 8.50 (d,1H), 12.50 (s,1H)** 9. 3,5-difluorophenyl H, H —CH₃ —COR₆ H OCH₂CH₃ — — 1.25 (t+d,6H), 3.65 (s,2H),4.25 (m,2H), 4.45 (m,1H), 6.95 (d,2H), 7.10 (m,1H), 8.05 (s,1H), 8.57(d,1H), 12.65 (s,1H)** 10. 3,5- difluorophenyl H, H —CH₃ —COR₆ —CH₃ OCH₃— — 1.27 (d,3H). 2.57 (s,3H), 3.50 (s,2H), 3.74 (s,3H), 4.36 (m,1H),6.96 (d,2H), 7.05 (m,1H), 8.53 (d,1H), 12.43 (s,1H)** 11. 3,5-difluorophenyl H, H —CH₃ —COR₆

OCH₃ — — 1.22 (d,6H), 1.33 (d,3H), 2.93 (m,1H), 3,54 (s,2H), 3.68(s,3H), 4.42 (m,1H), 6.98 (d,2H), 7.08 (m,1H), 7.29 (d,2H), 7.39 (d,2H),8.60 (d,1H), 12.68 (s,1H)** 12. 3,5- difluorophenyl H, H —CH₃ —COR₆—(CH₂)₂CH₃ NR₇R₈

— 0.89 (t,3H), 1.29 (m,3H), 1.31 (3H), 1.22-1.87 (m,10H), 3.10(t,2H),3.53 (s,2H), 3.67 (m,1H), 4.43 (m,1H), 6.98 (m,2H), 7.07 (m,1H), 7.41(d,1H), 8.54 (d,1H), 12.18 (s,1H)*** 13. 3,5- difluorophenyl H, H —CH₃—COR₆

OH — — 1.30 (d,3H), 2.98 (t,2H), 3.38 (t,2H), 3.50 (s,2H), 4.41 (m,1H),6.98 (d,2H), 7.07 (m,1H), 716-7.28 (m,5H), 8.53 (d,1H)*** 14. 3,5-difluorophenyl H, H —CH₃ —COR₆ CH₃(CH₂)₂— NR₇R₈

— 0.89 (t,3H), 1.30 (d,3H), 1,49 (m,4H), 1.95 (m,4H), 2.10 (m,2H), 3.11(m,2H), 3.30 (m,2H), 3.53 (s,2H), 4.49 (m,1H), 5.39 (s,1H), 6.98 (d,2H),7.09 (m,1H), 7.61 (t,1H), 8.54 (d,1H), 12.13 (s,1H)** 15. 3,5-difluorophenyl H, H CH₃(S) —COR₆ (CH₃)₂CH— OH — — 1.24 (d,6H), 1.27(d,3H), 3.51 (s,2H), 4.02 (m,1H), 4.38 (m,1H), 6.98 (d,2H), 7.09 (m,1H),8.56 (d,1H), 12.41 (s, 1H)*** 16. 3,5- difluorophenyl H, H CH₃(S) —COR₆(CH₃)₂CH— OCH₃ — — 1.25 (d,6H), 1.30 (d,3H), 3.53 (s,2H), 3.78 (s,3H),3.97 (m,1H), 4.36 (m,1H), 6.96-7.11 (m,3H), 8.56 (d,1H), 12.47 (s,1H)***17. 3,5- difluorophenyl OH, H(S) CH₃(S) —COR₆ (CH₃)₂CH— OCH₃ — — 1.25(d,6H), 1.30 (d,3H), 3.78 (s,3H), 3.97 (m,1H), 4.40 (m,1H), 5.04 (d,1H),6.55 (s,1H), 7.13 (m,3H), 8.34 (d,1H), 12.43 (s,1H)*** 18. 3,5-difluorophenyl H, H —(CH₂)₂CH₃(S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.85(t,3H),1.26 (d,6H), 1.28-1.65 (m,4H), 3.53 (m,2H), 3.78 (s,3H), 3.97 (m,1H),4.36 (m,1H), 6.96 (d,2H), 7.08 (m,1H), 8.49 (d,1H). 12.52 (s,1H)*** 19.3,5- difluorophenyl OH, H(S) —(CH₂)2CH₃(S) —COR₆ (CH₃)₂CH— OCH₃ — −53°0.80 (t,3H), 1.18 (m,2H), 1.22 (d,6H), 1.68 (m,2H), 3.78 (s,3H), 3.97(m,1H), 4.43 (m,1H), 5.05 (d,1H), 6.55 (d,1H), 7.13 (m,3H), 8.24 (d,1H),12.46 (s,1H)*** 20. 3,5- difluorophenyl OH, H(R) —(CH₂)₂CH₃(S) —COR₆(CH₃)₂CH— OCH₃ — −83° 0.82 (t,3H), 1.26 (d,6H), 1.26 (m,2H), 1.68(m,2H), 3.78 (s,3H), 3.97 (m,1H), 4.40 (m,1H), 5.07 (d,1H), 6.42 (d,1H),7.12 (m,3H), 8.27 (d,1H), 12.51 (s,1H)*** 21. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈

0.85 (t,3H), 1.22 (d,6H), 1.27-1.65 (m,1H), 3.19-3.30 (m,3H), 3.51-3.73(m,4H), 4.40 (m,1H), 7.09-6.90 (m,3H), 8.49 (d,1H), 12.22 (s,1H)*** 22.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂C— OCH₃ — 0.85(m,3H), 1.42 (s,9H), 1.30 (m,2H), 1.64 (m,2H), 3.29 (m,2H), 3.79 (s,3H),4,37 (m, 1H), 6.98-7.09 (m,3H), 8.46 (d,1H), 12.39 (s,1H)*** 23. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.85 (m,3H), 0.96 (t,2H), 0.95-1.69 (m,14H), 2.99 (t,2H), 3,54(m,2H), 3.77 (s,3H), 4.37 (m,1H), 6.97 (d,2H), 7.08 (m,1H), 8.48 (d,1H),12.51 (s,1H)*** 24. 3,5- difluorophenyl H, H CH₃(S) —COR₆ (CH₃)₂CH—OC(CH₃)₃ — — 1.26 (d,6H), 1.34 (d,3H), 1.51 (s,9H), 3.53 (s,2H), 3.90(m,1H), 4.39 (m,1H), 6.93 (d,2H), 7.07 (m,1H), 8.51 (s,1H), 12.40(s,1H)*** 25. 3,5- difluorophenyl H, H CH₃(CH₂)₃— (S) —COR₆ (CH₃)₂CH—OCH₃ — — 0.83 (t,3H), 1.25 (d,6H), 1.23-1.72 (m,6H), 3.55 (m,2H), 3.78(s,3H), 3.97 (m,1H), 4.35 (m,1H), 7.09-6.97 (m,3H), 8.47 (d,1H), 12.49(s,1H)*** 26. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH—NR₇R₈ CH₃, CH₃ −74° 0.87 (t,3H), 1.24 (d,6H), 1.29-1.67 (m,4H), 2.86(s,3H), 2.95 (s,3H), 3.22 (m,1H), 3.54 (m,2H), 4.41 (m,1H), 6.98 (d,2H),7.08 (m,1H), 8.49 (d,1H), 12.21 (s,1H)*** 27. 3,5- difluorophenyl OH,H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂C— OCH₃ — −54° 0.81 (t,3H), 1.22 (m,2H),1.43 (s,9H), 1.67 (m,2H), 3.78 (s,3H), 4.42 (m,1H), 5.05 (s,1H), 6.55(s,1H), 7.12 (m,3H), 8.22 (d,1H), 12.37 (s,1H)*** 28. 3,5-difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₃C— OCH₃ — −78° 0.82(t,3H), 1.25 (m,2H), 1.42 (s,9H), 1.69 (m,2H), 3.79 (s,3H), 4.40 (m,1H),5.07 (d,1H), 6.42 (d,1H), 7.13 (m,3H), 8.26 (d,1H), 12.41 (s,1H)*** 29.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ CH₃CH₂ OCH₃ — −70° 0.86(t,3H), 1.27 (t,3H), 1.29-1.35 (m,2H), 1.63 (m,2H), 3.10 (q,2H), 3.54(m,2H), 3,78 (s,3H), 4.39 (m,1H), 6.98 (d,2H), 7.07 (m,1H), 8.47 (d,1H),12.50 (s,1H)*** 30. phenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃— −51° 0.80 (t,3H), 1.16 (m,2H), 1.26 (s,9H), 1.68 (m,2H), 3.78 (s,3H),3.97 (m,1H), 4.43 (m,1H), 4.98 (d,1H), 6.31 (6,1H), 7.32 (m,5H), 8.14(d,1H), 12.46 (s,1H)*** 31. phenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — −110° 0.85 (t,3H), 1.28 (s,6H), 1.28 (m,2H), 1.68(m,2H), 3.78 (s,3H), 3.97 (m,1H), 4.44 (m,1H), 5.00 (d,1H), 6.17 (d,1H),7.30 (m,5H), 8.17 (d,1H), 12.51 (s,1H)*** 32. 3,5- difluorophenyl OH, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −66° 0.85 (m,3H), 1.28 (d,6H),1.30 (m,2H), 3.78 (s,3H), 3.96 (m,1H), 4.45 (m,1H), 5.20 and 5.22(2s,1H), 6.44-6.50 (2s,1H), 7.05 (m,1H), 7.19 (m,1H), 7.44 (m,1H), 8.19and 8.23 (2d,1H), 12.50 (s,1H)*** 33. 3,4- difluorophenyl OH, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −67° 0.82 (m,3H), 1.26 (d,6H),3.97 (m,1H), 4.41 (m,1H), 5.03 (m,1H), 6.35 and 6.48 (2s,1H), 7.27(m,1H), 7.42 (m,2H), 8.23 (m,1H), 12.48 (d,1H)*** 34. 2- chlorophenylOH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −127° 0.86 (t,3H), 1.26(d,6H), 1.29 (m,2H), 1.78 (m,2H), 3.78 (s,3H), 3.97 (m,1H), 4.46 (m,1H),5.33 (s,1H), 6.44 (s,1H), 7.29 (d,2H), 7.39 (d,1H), 7.45 (d,1H), 8.24(d,1H), 12.51 (s,1H)*** 35. 3- chlorophenyl OH, H(R) CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — −77° 0.83 (t,3H), 1.23 (d,6H), 1.29 (m,2H), 1.69(m,2H), 3.78 (s,3H), 3.96 (m,1H), 4.39 (m,1H), 5.04 (s,1H), 6.31 (s,1H),7.30-7.46 (m,4H), 8.24 (d,1H), 12.51 (s,1H)*** 36. 2- chlorophenyl OH, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −65° 0.86(t,3H), 1.26 (d,6H), 1.34(m,2H), 1.73 (m,2H), 3.78 (s,3H), 3.96 (m,1H), 4.46 (m,1H), 5,34 (d,1H),6.44 and 6,49 (2s,1H), 7.30 and 7.42 (2m,4H), 8.18 and 8.23 (2d,1H).12.50 (d,1H)*** 37. 2,6- difluorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — −66° 0.87 (t,3H), 1.26 (s,6H), 1.28 (m,2H). 3.79(s,3H), 3.98 (m,1H), 4.54 (m,1H), 5.28 (d,1H), 6.69 and 6.73 (2d,1H),7.06 (m,2H), 7.39 (m,1H), 8,11 and 8.21 (2d,1H). 12.54 (s,1H)*** 38.

OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −58° 0.81 (t,3H), 1.10(m,2H), 1.26 (d,6H), 1.60 (m,2H), 2.74 and 2.95,(dd,2H), 3.78 (s,3H),3.95 (m,1H), 4.15 (m,1H), 4.45 (m,1H), 5.69 (d,1H), 7.18 (m,5H), 7.80(d,1H), 12.44 (s,1H)*** 39.

OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −6° 0.84(t,3H), 1.18(m,2H), 1.26 (m,6H), 1.64 (m,2H), 2.70 and 2.93 (dd,2H), 3.79 (s,3H),3.98 (m,1H), 4.14 (m,1H), 4.45 (m,1H), 5.57 (d,1H), 7.09-7.21 (m,5H),7.95 (d,1H), 12.44 (s,1H)*** 40. cyclohexyl OH, H(S) CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — −59° 0.85 (t,3H), 1.11-1.18 (m,7H), 1.24 (d,6H),1.28 (m,1H), 1.65-1.69 (m,7H), 3.69 (d,1H), 3.78 (s,3H), 3.97 (m,1H),4.50 (m,1H), 5.46 (d,1H), 7.80 (d,1H), 12.44 (s,1H)*** 41. cyclohexylOH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — insoluble MeOH 0.85(t,3H), 1.25 (d,6H), 1.05-1.67 (m,15H), 3.70 (d,1H), 3.78 (s,3H), 3.96(m,1H), 4.45 (m,1H), 5.34 (d,1H), 7.82 (d,1H), 12.50 (s,1H)*** 42. 3,5-difluorophenyl OH, H(S) CH₃(CH₂)₃— (S) —COR₆ (CH₃)₂CH— OCH₃ — −49°0.78(t,3H), 1.18 (m,4H), 1.27 (d,6H), 1.71 (m,1H), 3.78 (s,3H), 3.97(m,1H), 4.42 (m,1H), 5.05 (m,1H), 6.56 (s,1H), 7.13 (m,3H), 8,23 (d,1H), 12.45 (s,1H)*** 43. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.80 (t,3H), 0.95 (m,2H), 1.13-1.69 (m,13H), 2.99 (d,2H), 3.77(s,3H), 4.42 (m,1H), 5.05 (s,1H), 6.55 (s,1H), 7.11 (m,3H), 8.24 (d,1H),12.51 (s,1H)*** 44. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆CH₃CH₂— OCH₃ — −55° 0.80 (t,3H), 1.19 (d,3H), 1.20 (m,1H), 1.69 (m,2H),3.09 (m,2H), 3.78 (s,3H), 4.41 (m,1H), 5.05 (s,1H), 6.55 (s,1H), 7.12(m,3H), 8.26 (d,1H), 12.45 (s,1H)*** 45. 3,5- difluorophenyl OH, H(R)CH₃(CH₂)₂— (S) —COR6 CH₃CH₂— OCH₃ — — 0.83 (t,3H), 1.22 (t,3H), 1.28(m,1H), 1.69 (m,2H), 3.09 (m,2H), 3.78 (s,3H), 4.40 (m,1H), 5.07 (s,1H),6.42 (s,1H), 7.12 (m,3H), 8.29 (d,1H), 12.51 (s,1H)*** 46. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃CH₂, CH₃CH₂— 0.85 (t,3H), 1.03-1.11 (m,6H), 1.20 (d,6H), 1,20-1.32 (m,2H), 1.60(m,2H), 3.18 (m,3H), 3.39 (m,2H), 3.55 (s,2H), 4.42 (m,1H), 6.98 (d,2H),7.07 (m,1H), 8.49 (d, 1H), 12.21 (s,1H)*** 47. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈

−66° 0.85 (t,3H), 1.21 (d,6H), 1.34-1.22 (m,2H), 1.64 (m,2H), 3.26(m,1H), 3.27 (s,2H), 3.50 (s,2H), 3.51 (s,2H), 3.57 (s,4H), 4.41 (m,1H),6.97 (d,2H), 7.08 (m,1H), 8.49 (d,1H), 12.25 (s,1H)*** 48. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃, H — 0.86(t,3H), 1.22 (d,6H), 1.35 (m,2H), 1.63 (m,2H), 2.75 (s,3H), 3.58 (d,2H),4.18 (m,1H), 4.47 (m,1H), 6.98 (d,2H), 7.07 (m, 1H), 7.69 (s,1H), 8.50(s,1H), 12.13 (s,1H)*** 49. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— NR₇R₈

— 0.86 (t,3H), 1.21 (d,6H), 1.34 (m,2H), 1.62 (m,2H), 2.20 (m,2H), 3.54(s,2H), 3.97 (m,2H), 4.38 (m,2H), 4.47 (m,1H), 6.97 (d,2H), 7.08 (m,1H),8.52 (d,1H), 12.08 (s,1H)*** 50. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆ phenyl OCH₃ — −112° 0.87 (t,3H), 1.30 (m,2H), 1.67 (m,2H), 3.56(s,2H), 3.67 (s,3H), 4.43 (m,1H), 6.98 (d,2H), 7.06 (m,1H), 7.44 (m,5H),8.56 (d,1H), 12.71 (s,1H)*** 51. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — −73° 0.79 (t,3H), 1.26 (d,6H), 1.73 (m,2H), 3.78(s,3H), 3.96 (m,1H), 4.36 (m,1H), 5.06 (s,4H), 6.56 (s,1H), 7.13 (m,3H),8.22 (d,1H), 12.46 (s,1H)*** 52. phenyl —OCH₃, H(S) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — −37° 086 (t,3H), 1.25 (m,2H), 1.30 (d,6H), 1.75 (m,2H),3.38 (s,3H), 3.79 (s,3H), 4.00 (m,1H), 4.47 (m,1H), 4.75 (s,1H), 7.33(m,5H), 8.22 (d,1H), 12.50 (s,1H)*** 53. phenyl —OCH₃, H(R) CH₃(CH₂)₂—(S) —COR₆ (CH₃)₂CH— OCH₃ — −113° 0.85 (t,3H), 1.27 (d,6H), 1.26 (m,2H),1.70 (m,2H), 3.30 (s,3H), 3.80 (s,3H), 3.98 (m,1H), 4.41 (m,1H), 4.77(s,1H), 7.30 (m,5H), 8.30 (d,1H), 12.50 (s,1H)*** 54. phenyl OH, CH₃,(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −66° 0.77 (t,3H), 1.10-1.17(m,2H), 1.35 (d,6H), 1.68 (s,3H), 3.85 (s,3H), 4.05 (m,1H), 4.45 (m,1H),6.30 (s,1H), 7.25-7.50 (m,5H), 8.00 (d,1H), 12.47 (s,1H)*** 55. phenylOH, CH₃, (R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −61° 0.90 (t,3H),1.28 (d,6H), 1.30 (m,2H), 1.65 (s,3H), 1.71 (m,2H), 3.83 (s,3H), 4.00(m,1H), 6.28 (s,1H), 7.22-7.50 (m,5H), 8.00 (d,1H), 12.50 (s,1H)*** 56.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ (CH₃)₂CH—,CH₃ — 0.86 (t,3H), 1.07 (m,6H), 1.11 (m,6H), 1.21 (m,2H), 1.62 (m,2H),2.66 (s,3H), 2.81 (s,3H), 3.27 (m,1H), 3.54 (s,2H), 3.77 (m,1H), 4.41(m,1H), 6.97 (d,2H), 7.07 (m,1H), 8.48 (d,1H), 12.20 (s,1H)*** 57. 3,5-difluorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃, CH₃ −119°0.72 (t,3H), 1.06 (m,1H), 1.16(m,1H), 1.27 (d,6H), 1.58 (m,2H), 2.10(s,3H), 3.78 (s,3H), 3.96 (m,1H), 4.37 (m,1H), 5.97 (s,1H), 7.34 and7.47 (2m,5H), 8.62 (s,1H), 12.49 (s,1H)*** 58. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃, OCH₃ — 0.86 (t,3H), 1.23(s,6H), 1.28-1.35 (m,2H), 1.64 (m,2H),3.20 (s,3H), 3.30 (m,1H), 3.52(s,3H), 4.42 (m,1H), 6.98 (d,2H), 7.08 (m,1H), 8.49 (d,1H), 12.23(s,1H)*** 59. 3,5- difluorophenyl H, H CH₃OCH₂— (S) —COR₆ (CH₃)₂CH— OCH₃— — 1.26 (t,3H), 3.28 (d,3H), 3.55 (s,2H), 3.57 (m,2H), 3.78 (s,3H),3.97 (m,1H), 4.64 (m,1H), 6.98 (d,2H), 7.08 (m,1H), 8.57 (d,1H), 12.54(s,1H)*** 60. 3,5- difluorophenyl OH, H(S) CH₃OCH₂— (S) —COR₆ (CH₃)₂CH—OCH₃ — — 1.25 (d,6H), 3.23 (s,2H), 3.59 (m,1H), 3.61 (m,1H), 3.78(s,3H), 3.96 (m,1H), 4.64 (m,1H), 5.09 (s,1H), 6,62 (s,1H), 7.13 (m,3H),8.23 (d,1H), 12.53 (s,1H)*** 61. 3,5- difluorophenyl OH, H(R) CH₃OCH₂—(S) —COR₆ (CH₃)₂CH— OCH₃ — — 1.26 (t,3H), 3.23 (s,2H), 3.62 (m,1H),(m,1H), 3.78 (s,3H), 3.97 (m,1H), 4,00 (m,1H), 5.10 (s,1H), 6.56 (s,1H),7.13 (m,3H), 8.26 (d,1H), 12.59 (s,1H)*** 62.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.86 (t,3H), 1.27 (d,6H),1.28 (m,2H), 1.62 (m,2H), 3.78 (s,3H), 3.97 (m,1H), 4.41 (m,1H), 4.94(m,1H), 5.33 (s,1H), 7.21 (m,5H), 8.13 (d,1H), 12.41 (s,1H)*** 63.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — 0.79 (t,3H), 1.12 (m,2H),1.27 (d,6H), 1.51 (m,2H), 3.78 (s,3H), 3.96 (m,1H), 4.37 (m,1H), 4.91(m,1H), 5.34 (s,1H), 7.30 (m,5H), 8.09 (d,1H), 12,38 (s,1H)*** 64. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃CH₃—, CH₃ —0.86 (t,3H), 1.05 (m,3H), 1.07 (d,6H), 1.08 (m,2H), 1.21 (m,2H), 2.82and 2.92 (2s,3H), 3.20 (m,2H), 3,30 (m,1H), 3,55 (s,2H), 4.41 (m,1H),6.98 (d,2H), 7.09 (m,1H), 8.49 (m,1H), 12.19 (s,1H)*** 65. phenyl H, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.85 (t,3H), 1,26 (d,6H), 1.34(m,2H), 3.46 (q,2H), 3.78 (s,3H), 3.97 (m,1H), 4.36 (m,1H), 7.24 (m,5H),8.38 (d,1H), 12.47 (s,1H)*** 66. 2,3- difluorophenyl OH, H CH₃(CH₂)₂—(S) —COR₆ (CH₃)₂CH— OCH₃ — −71° 0.86 (m,3H), 1.26 (d,6H), 1.28 (m,2H),1.72 (m,2H), 3.78 (s,3H), 3.96 (m,1H), 4.47 (m, 1H), 5.24 and 5.28(2d,1H), 6.55 and 6.62 (2d,1H), 7,17-7.36 (m,3H), 8.19 and 8.23 (dd,1H),12.49 (s,1H)*** 67. 2,3- difluorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — −68° 0.85 (m,3H), 1.26 (d,6H), 1.30 (m,2H), 1.72(m,2H), 3.78 (s,3H), 3,97 (m, 1H), 4.45 (m,1H), 5.20 and 5.23 (2s,1H),6.50 and 6.57 (2s,1H), 7.18 (m,3H), 8.19 and 8.25 (dd,1H), 12.48(s,1H)*** 68. phenyl

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −40° 0.97 (t,3H), 1.20 (d,6H),1.40 (m,2H), 1.80 (m,2H), 3.87 (s,3H), 4,05 (m,1H), 4.60 (m,1H), 7.60(m,2H), 7.80 (m,1H), 7.99 (m,2H), 9.30 (d,1H), 12.70 (s,1H)*** 69.

OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −66° 0.86 (t,3H), 1.30(d,6H), 1.25 (m,2H), 1.72 (m,2H), 3.81 (s,3H), 4.00 (m, 1H), 4.45(m,1H), 4.90 and 4.94 (dd,1H), 5.99 (m,2H), 6.13 and 6.26 (dd,1H), 6.86(m,3H), 8.14 (m,1H), 12.47 and 12.52 (d,1H)*** 70. phenyl —(OC(O)CH₃,H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.86 (t,3H), 1.24 (d,6H),1.26 (m,2H), 1.63 (m,2H), 2.11 (s,3H), 3.77 (s,3H), 3.95 (m,1H), 4.45(m,1H), 5.94 (s,1H), 7.38 (m,5H), 8.55 (d,1H), 2.48 (s,1H)*** 71. phenyl—(OC(O)CH₃, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.81 (1,3H),1.21 (d,6H), 1.22 (m,2H), 1.67 (m,2H), 2.86 (s,3H), 2.95 (s,3H), 3.22(m,1H), 4.44 (m,1H), 5.06 (m,1H), 6.54 and 6.41 (2s,1H), 7.13 (m,3H),8.26 (d,1H), 12.19 (s,1H)*** 72. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂—(S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.79 (t,3H), 1.25 (d,6H), 3.78 (s,3H), 3.96(m,1H), 4.36 (m,1H), 5.06 (s,1H), 6.56 (s,1H), 7.13 (m,3H), 8.22 (d,1H),12.46 (s,1H)*** 73. 3,5- difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — — 0.83 (t,3H), 1.26 (d,6H), 1.73 (m,2H), 3.78 (s,3H),3.95 (m,1H), 4.32 (m,1H), 5.08 (s,1H), 6.44 (s,1H), 7.12 (m,3H), 8.26(d,1H), 12.50 (s,1H)*** 74. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆ (CH₃CH₂)₂CH— OCH₃ — — 0.77 (m,6H), 0.83 (t,3H), 1.43-1.75 (m,8H),3.53 (m,2H), 3.70 (m,1H), 3.77 (s,3H), 4.36 (m,1H), 6.98 (d,2H), 7.08(m,1H), 8.46 (d,1H), 12.51 (s,1H)*** 75. 3,5- difluorophenyl

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.89 (t,3H), 1.28 (d,6H), 1.33(m,2H), 1.77 (m,2H), 3.78 (s,3H), 3.98 (m,1H), 4.56 (m,1H), 7.70 (m,3H),9.36 (d,1H), 12.62 (s,1H)*** 76. CH3S(CH2)2— OH, H CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — — 0.93 (t,3H), 1.38 (d,6H), 1.39 (m,2H), 1.74-1.90(m,2H), 2.10 (s,3H), 2.56 (s,2H), 3.85 (s,3H), 4.04 (m 1H), 4.08 (m,1H),4.51 (m,1H), 5.73 (d,1H), 7.97 (d,1H), 12.50 (s,1H)*** 77. (CH3)2CHCH2—OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.87 (m,9H), 1.27(d,6H), 1.26-1.39 (m,4H), 1.67 (m,3H), 3.78 (s,3H), 3.90 (m,2H), 4.45(m,1H), 5.49 (d,1H), 7.85 (d,1H), 12.43 (s,1H)*** 78. 3,5-difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃CH₂)₂CH— OCH₃ — −61°0.80 (m,9H), 1.25 (m,2H), 1.50 (m,2H), 1.70 (m,4H), 3.73 (m,1H), 3.80(s,3H), 4.45 (m,1H), 5.05 (s,1H), 6.55 (s,1H), 7.15 (m,3H), 8.25 (d,1H),12.45 (s,1H)*** 79. 3,5- difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆(CH₃CH₂)₂CH— OCH₃ — — 0.80 (m,6H), 0.85 (m,3H), 1.30 (m,2H), 1.50(m,2H), 1.75 (m,4H), 3.75 (m,1H), 3.85 (s,3H), 4.45 (m,1H), 5.11 (s,1H),6.45 (s,1H), 7.18 (m,3H), 8.31 (d,1H), 12.60 (s,1H)*** 80. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — −96° 0.78 (d,2H), 0.88 (t,3H), 1.20 (d,2H), 1.25-1.40 (m,2H),1.68 (m,2H), 2.90 (m,1H), 3.55 (m,2H), 3.82 (s,3H), 4.38 (m,1H),7.00-7.15 (m,3H), 8.50 (d,1H), 12.48 (s,1H)*** 81. 3,5- difluorophenylOH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — −56° 0.75 (m,2H), 0.82 (t,3H), 1.22 (m,2H), 1.70 (m,2H), 2.90(m,1H), 3.80 (s,3H), 4.42 (m,1H), 5.08 (s,1H), 6.48 (s,1H), 7.13 (m,3H),8.25 (d,1H), 12.48 (s,1H)*** 82. 3,5- difluorophenyl OH, H(R) CH₃(CH₂)₂—(S) —COR₆

OCH₃ — −84° 0.78 (m,2H), 0.90(t,3H), 1.20 (m,2H), 1.30 (m,2H), 1.70(m,2H), 2.90 (m,1H), 3.85 (s,3H), 4.40 (m,1H), 5.10 (s,1H), 6.42 (s,1H),7.18 (m,3H), 8.30 (d,1H), 12.55 (s,1H)*** 83. phenyl CH₃(CH₂)₂—, H(S)CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −25° 0.80 (t,3H), 0.86 (t,3H),1.26 (d,6H), 1.30-1.40 (m,2H), 1,65 (m,2H), 3.50 (m,1H), 3.80 (s,3H),3.95 (m,1H), 4.45 (m,1H), 7.20-7.30 (m,5H), 8.30 (d,1H), 12.45 (s,1H)***84. phenyl CH₃(CH₂)₂—, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ —0.80(t,3H), 0.85(t,3H), 1.18-1.30 (m,2H), 1.30 (d,6H), 1.60 (m,2H), 1.95(m,2H), 3.50 (m,1H), 3.80 (s,3H), 4.00 (m,1H), 4.30 (m,2H), 7.20-7.30(m,5H), 8.32 (d,1H), 12.45 (s,1H)*** 85. phenyl CH₃, H(S) CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — −17° 0.91 (t,3H), 1.30 (d,6H), 1.38(d,3H),1.30-1.45 (m,2H), 1.68 (m,2H), 3.80 (m,1H), 3.85 (s,3H), 4.00 (m, 1H),4.48 (m,1H), 7.21-7.30 (m,5H), 8.30 (d,2H), 12.48 (s,1H)*** 86. phenylCH₃, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.78 (t,3H), 1.14-1.25(m,2H), 1.30 (m,6H), 1.57 (m,2H), 3.72 (m,1H), 3.75 (s,3H), 3.98 (m,1H),4.31 (m,1H),7.24-7.40 (m,5H), 8.26 (d,1H), 12.45 (s, 1H)*** 87. phenyl

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.78 and 0.90 (2t,3H), 0.60-2.00(m,15H), 1.25 and 1.35 (2d,6H), 3.30 (m,1H), 3.80 (2s,3H), 4.00 (m,1H),4.25 and 4.45 (2m,1H), 7.20-7.35 (m,5H), 8.30 (m,1H), 12.45 (m,1H)***88. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈CH₃, CH₃ — 0.80 (t,3H), 1.25 (d,6H), 1,28 (m,2H), 1.75 (m,2H), 2.80(s,3H), 3.00 (s,3H), 3.25 (m,1H), 4.49 (m1H), 5.08 (s,1H), 6.55 (broads,1H), 7.13 (d,3H), 8.25 (d,1H), 12.15 (s,1H)*** 89. 3,5- difluorophenylOH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃, CH₃ −64° 0.88 (t,3H),1,22 (d,6H), 1.30 (m,2H), 1.68 (m,2H), 2.87 (s,3H), 2.98 (s,3H), 3.25(m,1H), 4.45 (m,H), 5.10 (s,1H), 6.42 (s,1H), 7.18 (m,5H), 8.30 (d,1H),12.20 (s,1H)*** 90. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ HOCH₃CH₃ — — 0.89 (t,3H), 1.28 (t,3H), 1.35 (m,2H), 1.65 (m,2H), 3.58(m,2H), 4.28 (m,2H), 4.40 (m,1IH), 6.98 (d,2H), 7.08 (t,1H), 8.05(s,1H), 8.50 (d,1H), 12.67 (s,1H)*** 91. cyclohexyl H, H CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — — 0.85 (t,3H), 0.90 (m,3H), 1.30 (m,2H), 1.30(d,6H), 1.60 (m,9H), 2.00 (m,2H), 3.80 (s,3H), 3.98 (m,1H), 4.36 (m,1H),8.08 (d1,1H), 12,40 (s,1H)*** 92.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.85 (t,3H), 1,28 (d,6H),1.30 (m,2H), 1.60 (m,1H), 3.60 (m,2H), 3.80 (s,1H), 4.00 (m,1H), 5.10(s,2H), 6.86-7.46 (m,9H), 8.18 (d,1H), 12.42 (s,1H)*** 93.3-hydroxyphenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.88(t,3H), 1.28 (d,6H), 1.26 (m,2H), 1.75 (m,2H), 3.50 (m,2H), 3.80 (s,3H),4.00 (m,1H), 4.40 (m,1H), 6.70-7.10 (m,4H), 8.25 (s,1H), 9.55 (s,1H),12.45 (s,1H)*** 94.

OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — −74° 0.89 (t,3H), 1.29(d,6H), 1.32 (m,2H), 1.67 (m,2H), 3.80 (s,3H), 4.00 (m,2H), 4.55 (m,1H),4.92 (d,1H), 5.51 (d,1H), 7.20-7.40 (m,5H), 7.80 (d,1H), 12.50 (s,1H)***95.

OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — +38° 0.90 (t,3H), 1.26(m,2H), 1,38 (d,6H), 1.69 (m,2H), 3.86 (s,3H), 4.05 (m,1H), 4.08 (m,1H),4.53 (m,1H), 4.92 (m,1H), 5.33 (m,1H), 5,41 (d,1H), 7.25-7.45 (m,5H),8.05 (d,1H), 12.50 (s,1H)*** 96. Ph(CH₂)₂— OH, H(R) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — −8° 0.86 (t,3H), 1.25 (d,6H), 1.28 (m,2H), 1.68 (m,2H),1.74 (m,2H), 2.51 (m,2H), 3,78 (s,3H), 3.91 (m,1H), 3.97 (m,1H), 4.43(m,1H), 5.65 (s,1H), 7.13-7.26 (m,5H), 7.91 (d,1H), 12.47 (s,1H)*** 97.(CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.90 (t,3H),0.93 (s,9H), 1.30 (d,6H), 1.32 (m,2H), 1.71 (m,2H), 3.58 (d,1H), 3.82(s,3H), 4.02 (m,1H), 4.52 (m,1H), 5.60 (d,1H), 7.82 (d,1H), 12.45(s,1H)*** 98. phenyl F, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — —0.87 (t,3H), 1.22 (d,6H), 1.32 (m,2H), 1.70 (m,2H), 3.78 (s,3H), 3.98(m,1H), 4.52 (m,1H), 5.90 and 6.00 (2s,1H), 7.44 (m,5H), 8.70 (d,1H),12.55 (s,1H)*** 99. phenyl F, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ —— 0.90 (t,3H), 1.24 (m,2H), 1.30 (s,6H), 1.77 (m,2H), 3.85 (s,3H), 4.05(m,1H), 4.48 (m,1H), 5.97 and 6.05 (2s,1H), 7.50 (m,5H), 8.80 (d,1H),12.62 (s,1H)*** 100. (CH₃)₂CH— OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH—OCH₃ — — 0.77 (d,3H), 0.85 (t,3H), 0.95 (d,3H), 1.26 (d,6H), 1.32(m,2H), 1.70 (m,2H), 1.95 (m,1H), 3.72 (m,1H), 3.78 (s,3H), 3.98 (m,1H),4.50 (m,1H), 5.45 (s,1H), 7.80 (d,1H), 12.45 (s,1H)*** 101. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃CH₃ — — 0.92 (t,3H), 1.36 (m,2H), 1.71 (m,2H), 2.96 (m,2H), 3.44(m,2H), 3.61 (5,1H), 3.84 (s,3H), 4.47 (rn,1H), 7.12 (d,2H), 7.16(t,1H), 7.23-7.36 (m,5H), 8.53 (d,1H), 12.55 (s,1H)*** 102. 3,5-difluorophenyl

CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.81 (m,2H), 0.97 (t,3H), 1.25 (m,2H), 1,39(m,2H), 1.83 (m,2H),2.95 (m,1H), 3.86 (s,3H), 4.61 (m,1H), 7.78 (m,3H), 9.40 (d,1H), 12.68(s,1H)*** 103. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.92 (t,3H), 1.34-1.43 (m,7H), 1.69-1.84 (m,5H), 2.00 (m,2H),3.61 (d,2H), 3.69 (m,1H), 3.84 (s,3H), 4.47 (m,1H), 7.06 (d,2H), 7.25(1,1H), 8.55 (d,1H), 12.55 (s, 1H)*** 104. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆ (CH₃)₃CCH₂— OCH₃ — — 0.86 (t,3H), 0.91 (s,9H), 1.34(m,2H), 1.66 (m,2H), 3.12 (m,2H), 3.58 (m,2H), 3.76 (s,3H), 4.40 (m,1H),7.02 (d,2H), 7.09 (t,1H), 8.49 (d,1H), 12.50 (s, 1H)*** 105. 3,5-difluorophenyl

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃, CH₃ — 0.89 (t,3H), 1.23(d,6H), 1.37 (m,2H), 1,73 (m,2H), 2.88 (s,3H), 2.95 (s,3H), 3.24 (m,1H),4.58 (m,1H), 7.72 (m,3H), 9.36 (d,1H), 12.36 (s,1H)*** 106. (CH₃)₃C— OH,H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR₇R₈ CH₃, CH₃ — 0.87 (t,3H), 0.90(s,9H), 1.25 (d,6H), 1.33 (m,2H), 1.68 (m,2H), 2.89 (s,3H), 2.97 (s,3H),3.57 (s,1H), 4.54 (m,1H), 5.56 (s,1H), 7.84 (d,1H), 12.15 (s,1H)*** 107.3-chlorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.87(t,3H), 1.20 (m,2H), 1.22 (d,6H), 1.70 (m,2H), 3.80 (s,3H), 4.00 (m,1H),4.43 (m,1H), 5.02 (s,1H), 6.44 (s,1H), 7.30 (m,3H), 7.45 (s,1H), 8.20(d,1H), 12.45 (s,1H)*** 108. (CH₃CH₂)₂CH— OH, H(S) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — — 0.86 (t,3H), 0.93 (m,6H), 1.24 (m,2H), 1.32 (d,6H),1.38 (m,4H), 1.55 (m,1H), 1.72 (m,2H), 3.78 (s,3H), 3.98 (m,1H), 4.05(m,1H), 4.55 (m,1H), 5.55 (d,1H), 7.92 (d,1H), 12.50 (s,1H)*** 109.(CH₃CH₂)₂CH— OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.80(t,3H), 0.90 (m,6H), 1.20 (m,2H), 1.30 (d,6H), 1.34 (m,4H), l.55 (m,1H),1.74 (m,2H), 3.86 (s,3H), 4.00 (m,2H), 4.53 (m,1H), 5.42 (d,1H), 8.00(d,1H), 12.54 (s,1H)*** 110. 3,5- difluorophenyl OH, H CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — — 0.82 (m,3H), 1.10 (m,2H), 1.27 (m,6H), 1.61(m,2H), 2.83 and 2.95 (2m,1H), 3.77 (s,3H), 3.96 (m,1H), 4.21 (m,1H),4.43 (m,1H), 5.68 and 5.81 (2d,1H), 6.93-7.01 (M,3H), 7.84 and 7.97(2d,1H), 12.46 (s,1H)*** 111. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.87 (t,3H), 1.32 (m,2H), 1.61 (m,2H), 3.55 (m,2H), 3.83(s,3H), 4.39 (m,1H), 4.61 (s,2H), 6.98 (d,2H), 7.10 (t,1H), 7,30 (m,5H),8.49 (d,1H), 12.55 (s,1H)*** 112. 3,5- difluorophenyl OH, H(S)CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.81 (t,3H), 1.22 (m,2H), 1.68 (m,2H), 3.83 (s,3H), 4.40(m,1H), 4.44 (s,2H), 5.06 (s, 1H), 6.56 (s,1H), 7.15-.7.24 (m,3H), 7.32(m,5H), 8.24 (d,1H), 12.52 (s,1H)*** 113. 3,5- difluorophenyl OH, H(R)CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.83 (t,3H), 1,24 (m,2H), 1.69 (m,2H), 3.82 (s,3H), 4.37(m,1H), 4.48 (s,2H), 5.07 (s,1H), 6.55 (s,1H), 7.13 (m,3H), 7.33 (m,5H),8.26 (d,1H), 12.59 (s,1H)*** 114.

OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.70-0.80 (m,3H),1.12-1.20 (m,3H), 1.20-1.35 (m,2H), 1.30 (m,6H), 1.60 (m,2H), 3.15(m,1H), 3.80 (s,3H), 4.05 (m,2H), 4.40 (m,1H), 5.43, 5.55 and 5.80(3d,1H), 6.95-7.30 (m,5H), 7.60 and 7.95 (2d,1H), 12.30.1 2.50 (m,1H)***115.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.88 (t,3H), 1.27 (d,6H),1.35 (m,2H), 1.67 (m,2H), 3.50 (m,2H), 3.80 (s,3H), 4.00 (m,1H), 4.38(m,1H), 7.00 (d,1H), 7.25 (d,1H), 7.50 (4,1H), 8.35 (d,1H), 12.50(s,1H)*** 116. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆ phenylOCH₃ — — 0.84 (t,3H), 1,19-1.31 (m,2H), 1.74 (m,2H), 3.69 (s,3H), 4.50(m,1H), 5.09 (m,1H), 6.58 (s,1H), 7.50 (broads,3H), 7.45 and 7.51(2s,5H), 8.31 (d,1H), 12.75 (s,1H)*** 117. 3,5- difluorophenyl OH, H(R)CH₃(CH₂)₂— (S) —COR₆ phenyl OCH₃ — — 0.86 (t,3H), 1.26-1.36 (m,2H), 1.75(m,2H), 3.69 (s,3H), 4.48 (m,1H), 5.11 (s,1H), 6.59 (s,1H), 7.14(broads,3H), 7.34 and 7.49 (2s,5H), 8.35 (d,1H), 12.84 (s,1H)*** 118.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₂CH₃ — — 0.87(t,3H), 1.32 (d,6H), 1.35 (m,2H), 1.61 (m,2H), 3.54 (m,2H,), 3.96(m,1H), 4,24 (m,2H), 4.37 (m,1H), 6.96 (d,2H), 7.07 (t,1H), 8.46 (d,1H),12.50 (s,1H)*** 119. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CCH₂— OCH₂ — — 0.81 (t,3H), 0.90 (s,9H), 1.21 (m,2H), 1.69(rn,2H), 3.08 (m,2H), 3.77 (s,3H), 4.44 (m,1H), 5.07 (s,1H), 7.17(m,3H), 8.28 (d,1H)*** 120. 3,5- difluorophenyl OH, H(R) CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CCH₂— OCH₂ — — 0.87 (t,3H), 0.97 (s,9H), 1.24 (m,2H), 1.72(m,2H), 3.12 (m,2H), 3.80 (s,3H), 4.41 (rn,1H), 5.10 (d,1H), 6.45(d,1H), 7.10 (m,3H), 8.30 (d,1H), 12.50 (s,1H)*** 121. 3- chlorophenyl

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.91 (t,3H), 1.32 (d,6H), 1.37(m,2H), 1.78 (m,2H), 3.79 (s,3H), 4.02 (m,1H), 4.56 (m,1H), 7.63 (t,1H),7.80 (d,1H), 7.94 (d,1H), 7.99 (s,1H), 9.33 (d,1H), 12.66 (s,1H)*** 122.2- benzyloxyphenyl OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.85(m,3H), 1.26 (m,2H), 1.28 (d,6H), 1.69 (m,2H), 3.78 (s,3H), 3.98 (m,1H),4.47 (m,1H), 5.22 (s,2H), 5.33 (2d,1H), 6.07 and 6.11 (2d,1H), 6.90-7.50(m,8H) 8.00 (m,1H), 12.48 (s,1H)*** 123.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.87 (t,3H), 1.28 (d,6H),1.36 (rn,2H), 1.67 (m,2H), 3.70 (m,2H), 3.78 (s,3H), 3.98 (m,1H), 4.36(m,1H), 6.90 and 6.92 (d+t,2H), 7.33 (d,1H), 8.41 (d,1H), 12.58(s,1H)*** 124. 2,3- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — — 0.85 (t,3H), 1.27 (d,6H), 1.31 (m,2H), 1.72 (m,2H),3.79 (s,3H), 3.97 (m,1H), 4.49 (m,1H), 5.25 (s,1H), 6.62 (broad s 1H),7.22 (m,2H), 7.36 (m,1H), 8.21 (d,1H), 12.53 (s,1H)*** 125. 2,3-difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.89(t,3H), 1.29 (d,6H), 1.33 (m,2H), 1.71 (m,2H), 3.80 (s,3H), 3.96 (m,1H),4.47 (m,1H), 5.30 (d,1H), 6.58 (d,1H), 7.19 (m,2H), 7.26 (m,1H), 8.26(d,1H), 12.57 (s,1H)*** 126. 2,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— OCH₃ — — 0.86 (t,3H), 1.28 (d,6H), 1.31 (m,2H), 1.72(m,2H), 3.79 (s,3H), 3.98 (m,1H), 4.48 (m,1H), 5.21 (s,1H), 6.59 (broads 1H), 7.21 (m,3H), 8.22 (d,1H), 12.51 (s,1H)*** 127. 2,5-difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.90(t,3H), 1.34 (d,6H), 1.39 (m,2H), 1.77 (m,2H), 3.83 (s,3H), 4.06 (m,1H),4.50 (m,1H), 5.36 (d,1H), 6.56 (d,1H), 7.25 (m,3H), 8.32 (d,1H), 12.58(s,1H)*** 128. 2- hydroxyphenyl OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH—OCH₃ — — 0.91 (m,3H), 1.28 (m,2H), 1.30 (d,6H), 1.80 (m,2H), 3.85(s,3H), 4.07 (m,1H), 4.53 (m,1H), 5.31 and 5.35 (2s,1H), 6.87 (m,2H),7.13 (m,1H), 7.27 (rn,1H), 8.17 (m,1H), 9.66 (broad s 1H), 12.49(s,1H)*** 129.

OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.92 (t,3H), 1.27(m,2H), 1.32 (d,6H), 1.77 (m,2H), 3.84 (s,3H), 4.05 (m,1H), 4.34 (m,1H),4.59 (m,1H), 4.64 (m,1H), 7.08 (d,1H), 8.25 (d,1H), 12.50 (s,1H)*** 130.

OH, H(R) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.94 (t,3H), 1.37(D,6H), 1.42 (m,2H), 1.78 (m,2H), 3.85 (s,3H), 4.06 (m,1H), 4.28 (m,1H),4.56 (m,1H), 4.66 (m,1H), 7.10 (d,1H), 8.40 (d,1H), 12.58 (s,1H)*** 131.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— NR7R8

— 0.87 (t,3H), 1.28 (d,6H), 1.29 (m,2H), 1.63 (m,2H), 2.98 (m,2H), 3.52(m,2H), 3.62 (m,2H), 4.20 (m,1H), 4.46 (m,1H), 6.98 (d,2H), 7.10 (t,1H),7.28 (m,2H), 7.70 (t,1H), 7.90 (m,2H), 8.53 (m,2H), 12.20 (s,1H)*** 132.

OH, H(S) CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.33 (m,2H), 0.37(m,2H), 0.90 (t,3H), 1.09 (rn,1H), 1.30 (s,6h), 1.34 (m,2H), 1.71(m,2H), 3.66 (m,1H), 3.83 (s,3H), 4.03 (m,1H), 4.59 (m,1H), 5.55 (d,1H),7.88 (d,1H), 12.52 (s,1H)*** 133.

OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.30 (m,2H), 0.38 (m,2H),0.86 (t,3H), 1.03 (m,1H), 1.27 (d,6H), 1.30 (m,2H), 1.67 (m,2H), 3.55(m,1H), 3.78 (s,3H), 3.99 (m,1H), 4.50 (rn,1H), 5.37 and 5.50 (2d,1H),7.76 and 7.84 (2d,1H), 12.50 (s,1H)*** 134.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.87 (t,3H), 1.28 (d,6H),1.36 (rn,2H), 1.67 (m,2H), 3.75 (m,2H), 3.77 (s,3H), 3.98 (m,1H), 4.42(m,1H), 7.33 (rn,2H), 7.50 (s,1H), 7.83 (d,1H), 7.94 (d,1H), 8.52(d,1H), 12.58 (s,1H)*** 135. 3- chlorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆(CH₃)₂CH— OCH₃ — — 0.87 (rn,3H), 1.25 (m,2H), 1.28 (s,6H), 1.75 (m,2H),3.83 (s,3H), 4.01 (m,1H), 4.48 (m,1H), 4.94 (2d,1H), 6.14 and 6.29(2d,1H), 6.67 (rn,1H), 6.87 (rn,2H), 7.14 (m,1H), 8.11 (m,1H), 8.41(2s,1H), 12.52 (d,1H)*** 136.

OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.87 (m,3H), 1.24 (s,6H),1,26 (rn,2H), 1.73 (rn,2H), 3.80 (s,3H), 3.98 (rn,1H), 4.45 (rn,1H),5.08 (m,1H), 6.17 and 6.27 (2d, 1H), 7.11 (d,1H), 7.41-7.48 (m,2H), 8.14(m,1H), 12.50 (d,1H)*** 137.

H, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.86 (t,3H), 1.28 (d,6H),1.29 (m,2H), 1.61 (m,2H), 2.47 (m,2H), 2.81 (m,2H), 3.88 (s,3H), 4.00(rn,1H), 4.46 (m,1H), 6.98 (s,1H), 7.23 (s,1H), 7.43 (s,1H), 8.16(d,1H), 12.44 (s,1H)*** 138. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆ (CH₃)₂CH— NR7R8

— 0.92 (t,3H), 1.31 (d,6H), 1.40 (rn,2H), 1.71 (m,2H) 2.86 (rn,2H), 3,54(m,2H), 3,60 (m,2H), 4.24 (rn,1H), 4.50 (m,1H), 7.13 (d,2H), 7.18(t,1H), 7.25-7.36 (rn,5H), 7.80 (d,1H), 8.56 (d,1H), 12.25 (s,1H)***139.

OH, H CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.84 (t,1H), 1.20 (m,2H),1.22 (d,6H), 1.70 (rn,2H), 3.80 (s,3H), 3.99 (m,1H), 4.45 (rn,1H), 5.07(s,1H), 6.49 (d,1H), 7.37 (d,1H), 7.80 (d,1H), 8.27 (d,1H), 8.48 (d,1H),8.61 (s,1H), 12.42 (broad s,1H)*** 140.

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— OCH₃ — — 0.95 (t,3H), 1.35 (d,6H), 1.42(rn,2H), 1.85 (m,2H), 3.82 (s,3H), 4.05 (m,1H), 4.62 (m,1H), 7.70(d,1H), 8.40 (d,1H), 8.90 (d,1H), 9.19 (s,1H), 9.35 (d,1H), 12.65(s,1H)*** 141.

CH₃(CH₂)₂— (S) —COR₆ (CH₃)₂CH— — — 0.95 (t,3H), 1.38 (d,6H), 1.41(m,2H), 1.85 (rn,2H), 3.84 (s,1H), 4.04 (m,1H), 4.58 (rn,1H), 6.86(s,1H), 7.86 (s,lH), 8.23 (s,1H), 9.20 (d,1H), 12.60 (s,1H)*** 142. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.88 (t,3H), 1.35 (rn,2H), 1.69 (m,2H), 3.61 (rn,2H), 3.68(s,3H), 4.46 (m,1H), 7.08 (d,2H), 7.09(t,1H), 7.60 (m,3H), 7.96 (m,3H),7.99 (s,1H), 8.52 (d,1H), 12.78 (s,1H)*** 143. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.89 (t,3H), 1.30 (rn,2H), 1.68 (m,2H), 3.56 (m,2H), 3.67(s,3H), 4.43 (m,1H), 5.13 (s,2H), 6.98 (d,2H), 7.08-7.47 (m,10H), 8.58(d,1H), 12.65 (s,1H)*** 144. 3,5- difluorophenyl H, H CH₃ —(CH₂)₃CH₃—COR₆ OCH₃ — — 0.88 (t,3H), 1.32 (d,3H), 1.66 (m,2H), 2.95 (m,2H), 3.54(s,2H), 3.76 (s,3H), 4.47 (m,2H), 6.97 and 7.10 (2m,3H), 8.63 (d,1H),12.66 (s,1H)*** 145. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)

—COR₆ OCH₃ — — 0.87 (t,3H), 0.98 (m,2H), 1.13 (m,3H), 1.27 and 1.36(2m,2H), 1.59-1.70 (m,8H), 2.83 and 2.93 (2m,2H), 3.28 (s,2H), 3.78(s,3H), 4.44 (m,1H), 6.96 and 7.09 (m,3H), 8.54 (d,1H), 12.66 (s,1H)***146. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —(CH₃)₂CH₃ —COR₆ OCH₃ — —0.87 (t,3H), 1.27 (d,6H), 1.35 (m,2H), 1.64 (m,2H), 3.54 (s,2H), 3.77(s,3H), 3.90 (m,1H), 4.45 (rn,1H), 6.96-7.09 (rn,3H), 8.53 (d,1H), 12.69(s,1H)*** 147. 3,5- difluorophenyl OH, H(S) CH₃(S) —(CH₃)₂CH₃ —COR₆ OCH₃— — 1.18 (d,6H), 1.32 (d,3H), 3.77 (s,3H), 3.91 (m,1H), 4.48 (m,1H),5.05 (s,1H), 6.53 (s,1H), 7.12 (m,3H), 8.37 (d,1H), 12.61 (s,1H)*** 148.3,5- difluorophenyl H, H CH₃(S) —CH(CH₃)₂ —COR₆ OCH₃ — — 1.15 (d,6H),1.32 (d,3H), 3.53 (s,2H), 3.77 (s,3H), 4.04 (m,1H), 4.47 (m,1H),6.97-7.09 (m,3H), 8.59 (d,1H), 12.66 (s,1H)*** 149. 3,5- difluorophenylOH, H(R) CH₃(S) —CH(CH₃)₂ —COR₆ OCH₃ — — 1.17 (d,6H), 1.35 (d,3H), 3.77(s,3H), 3.91 (m,1H), 4.49 (rn,1H), 5.04 (s,1H), 6.47 (s,1H), 7.12(m,3H), 8.37 (d,1H), 12.62 (s,1H)*** 150. 3,5- difluorophenyl OH, H(S)CH₃(CH₂)₂— (S) —CH(CH₃)₂ —COR₆ OCH₃ — −73° 0.81 (t,3H), 1.18 (d,6H),1.22 (rn,2H), 1.71 (m,2H), 3.77 (s,3H), 3.90 (m,1H), 4.50 (rn,1H), 5.06(s,1H), 6.54 (s,1H), 7.12 (m,3H), 8.30 (d,1H), 12.66 (s,1H)*** 151. 3,5-difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —CH(CH₃)₂ —COR₆ OCH₃ — −104° 0.83(t,3H), 1.19 (d,6H), 1.22 (m,2H), 1.70 (m,2H), 3.77 (s,3H), 3.91(rn,1H), 4.48 (rn,1H), 5.07 (s,1H) 6.42 (s,1H), 7.12 (rn,3H), 8.34(d,1H), 12.67 (s,1H)*** 152. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)phėnyle —COR₆ OCH₂CH₃ — −88° 0.86 (t,3H), 1.19 (t,3H), 1.29 (rn,2H),1.67 (rn,2H), 3.57 (s,2H), 4.18 (m,2H), 4.47 (m,1H), 6.98 and 7.10(m,3H), 7.42 and 7.68 (2s,5H), 8.55(d,1H), 12.81 (s,1H)*** 153. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —CH(CH₃)₂ —COR₆ OCH₂CH₃ — −120°0.87(t,3H), 1.18 (d,6H), 1.27 (t,3H), 1.30 (m,2H), 1,65 (m,2H), 3.55(s,2H), 3.90 (m,1H), 4.25 (m,2H), 4.43 (m,1H), 6.80-7.13 (m,3H), 8.53(d,1H), 12.66 (s,1H)*** 154. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S)—CH(CH₃)₂ —COR₆ OCH₃ — — 0.80 (t,3H), 0.90(t,3H), 1.22 (rn,2H), 1.68 and1.72 (2rn,4H), 2.98 (m,2H), 3.78 (s,3H), 4.52 (m,1H), 5.06 (s,1H), 6.55(s,1H), 7.17 (rn,3H), 8.31 (d,1H), 12.68 (s,1H)*** 155. 3,5-difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —(CH₂)₂CH₃ —COR₆ OCH₃ — — 0.80(t,3H), 0.90(3,3H), l.22 (m,2H), 1.66 and 1.73 (2m,4H), 2.98 (rn,2H),3.78 (s,3H), 4.49 (m,1H), 5.09 (s,1H), 6.43 (s,1H), 7.14 (rn,5H), 8.38(d,1H), 12.68 (s,1H)*** 156. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—(CH₂)₂CH₃ —COR₆ OCH₃ — −85° 0.89 (2t,6H), 1.37 (rn,2H), 1.63 (m,4H),2.95 (m,2H), 3.55 (s,2H), 3.76 (s,3H), 4.43 (rn,1H), 6.80-7.12 (rn,3H),8.55 (d,1H), 12.68 (s 1H)*** 157. 3,5- difluorophenyl H, H CH₃(CH₂)₂—(S) —CH₂CH₃ —COR₆ OCH₃ — −112° 0.88(t,3H), 1.30(t,3H), 1.37 (m,2H), 1.63(m,2H), 2.98 (m,1H), 3.56 (s,2H), 3.78 (s,3H), 4.50 (m,1H), 6.81-7.25(m,3H), 8.56 (d,1H), 12.71 (s,1H)*** 158. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —CH₂CH(CH₃)₂ —COR₆ OCH₃ — −99° 0.89 (t+d,12H), 1.29(m,2H), 1.66 (rn,2H), 2.05 (rn,1H), 2.86 (m,2H), 3.56 (s,2H), 3.78(s,3H), .46 (m,1H), 7.06-7.15 (rn,3H), 8.64 (d,1H), 12.68 (s,1H)*** 159.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —CH₃ —COR₆ OCH₃ — −126°0.88(t,3H), 1.29 (m,2H), 1.65 (rn,2H), 2.55 (s,3H), 3.56 (s,2H), 3.78(s,3H), 4.45 (rn,1H), 6.99-7.14 (rn,5H), 8.55 (d,1H), 12.68 (s,1H)***160. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —CH₂CH₃ —COR₆ OCH₃ — —0.82 (t,3H), 1.20 (d,6H), 1.26 (m,2H), 1.72 (rn,2H), 2.99 (m,2H), 3.78(s,3H), 4.49 (m,1H), 5.10 (s,1H), 6.43 (s,1H), 7.16 (rn,3H), 8.36(d,1H), 12.70 (s,1H)*** 161. 3,5- difluorophenyl OH, H(R) CH₃(CH₂)₂— (S)—CH₂CH₃ —COR₆ OCH₃ — — 0.89(t,3H), 1.24 (d,6H), 1.28 (m,2H), 1.77(rn,2H), 3.04 (m,2H), 3.83 (s,3H), 4.52 (m,1H), 5.15 (s,1H), 6.48(s,1H), 7.18 (rn,3H), 8.40 (d,1H), 12.65 (s,1H)*** 162. 3,5-difluorophenyl

CH₃(CH₂)₂— (S) —CH₂CH₃ —COR₆ OCH₃ — — 0.92(1,3H), 1.20 (t,3H), 1.38(m,2H), 1.78 (m,2H), 3.00 (m,2H), 3.80 (s,3H), 4.64 (rn,1H), 7.72(m,3H), 9.45 (d,1H), 12.95 (s,1H)*** 163. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂—(S) —CH₂CH₃ —COR₆ OCH₃ — — 0.87 (t,3H), 0.91 (s,9H), 1.21 (t,3H), 1.27(m,2H), 1.69 (m,2H), 3.01 (m,2H), 3.57 (d,1H), 3.78 (s,3H), 4.57(rn,1H), 5.56 (d,1H), 7.85 (d,1H), 12.63 (s,1H)*** 164. (CH₃)₃C—

CH₃(CH₂)₂— (S) —CH₂CH₃ —COR₆ OCH₃ — — 0.95 (t,3H), 1.34 (s,9H), 1.35(t,3H), 1.40 (m,2H), 1.75 (m,2H), 3.04 (m,2H), 3.98 (s,3H), 4.62(rn,1H), 9.03 (d,1H), 12.85 (s,1H)*** 165. 3,5- difluorophenyl OH, H(S)CH₃(CH₂)₂— (S) —CH₃ —COR₆ OCH₃ — — 0.82 (t,3H), 1.26 (m,2H), 1.69(rn,2H), 2.63 (s,3H), 3.77 (s,3H), 4.50 (m,1H), 5.07 (d,1H), 6.55(d,1H), 7.16 (rn,3H), 8.31 (d,1H), 12.65 (s,1H)*** 166. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —CH₂C(CH₃)₃ —COR₆ OCH₃ — — 0.87(t,3H), 0.94 (s,9H), 1.31 (m,2H), 1.66 (m,2H), 2.89-3.05 (m,2H), 3.59(s,2H), 3.77 (s,3H), 4.48 (m,1H), 6.98 (d,2H), 7.10 (t,1H), 8.54 (d,1H),12.65 (s,1H)*** 167. 3,5- difluorophenyl

CH₃(CH₂)₂— (S) —CH₃ —COR₆ OCH₃ — — 0.90 (t,3H), 1.38 (m,2H), 1.75(rn,2H), 2.63 (s,3H), 3.78 (s,3H), 4,61 (m,1H), 7.69 (m,3H), 9.43(d,1H)*** 168. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S) —CH₂C(CH₃)₃—COR₆ OCH₃ — — 0.81 (t,3H), 0.92 (s,9H), 1.20 (m,2H), 1.70 (m,2H), 2.90-2.98 (rn,2H), 3.77 (s,3H), 4.50 (rn,1H), 5.08 (d,1H), 6.52 (d,1H), 7.12(rn,3H), 8.30 (d,1H), 12.60 (s,1H)*** 169. 3,5- difluorophenyl OH, H(R)CH₃(CH₂)₂— (S) —CH₂C(CH₃)₃ —COR₆ OCH₃ — — 0.84 (t,3H), 0.93 (s,9H), 1.26(rn,2H), 1.71 (m,2H), 2.90- 3.00 (m,2H), 3.80 (s,3H), 4.47 (m,1H), 5.08(d,1H), 6.43 (d,1H), 7.17 (rn,3H), 8.35 (d,1H), 12.60 (s,1H)*** 170.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)

—COR₆ OCH₂CH₃ — — 0.89 (t,3H), 1.27 (t,3H), 1.29 (rn,2H), 1.66 (m,2H),1.97 (rn,2H), 2.63 (m,2H), 3.00 (rn,2H), 3.57 (s,2H), 4.25 (m,2H), 4.45(m,1H), 6.99 (d,2H), 7.09 (t,1H), 7.19-7.27 (rn,5H), 8,55 (d,1H), 12.68(s,1H)*** 171. 3,5- difluorophenyl OH, H(S) CH₃(CH₂)₂— (S)

—COR₆ OCH₃ — — 0.82 (t,3H), 1.18 (m,2H), 1.22 (t,3H), 1.67 (m,2H), 1.90(m,2H), 2.61 (m,2H), 3.00 (rn,2H), 4.23 (rn,2H), 4.47 (rn,1H), 5.06(d,1H), 6.54 (d,1H), 7.10-7.32 (m,8H), 8.28 (d,1H), 12.60 (s,1H)*** 172.3,5- difluorophenyl OH, H(R) CH₃(CH₂)₂— (S)

—COR₆ OCH₂CH₃ — — 0.82(t,3H), 1.24 (t,3H), 1.29 (m,2H), 1.68 (m,2H),1.91 (m,2H), 2.61 (m,2H), 2.99 (rn,2H), 4.21 (m,2H), 4.46 (m,1H), 5.07(d,1H), 6.40 (d,1H), 7.07-7.31 (m,8H), 8.32 (d,1H), 12.60 (s,1H)*** 173.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)

—COR₆ OCH₂CH₃ — — 0.85 (t,3H), 1.26 (t,3H), 1.27 (m,2H), 1.59 (m,8H),2.56 (m,2H), 2.99 (m,2H), 3.54 (m,2H), 4.23 (m,2H), 4.43 (m,1H), 6.98(d,2H), 7.09 (t,1H), 7.14-7.30 (m,5H), 8.52 (d,1H), 12.82 (s,1H)*** 174.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —(CH₂)₄CH(CH₃)₂ —COR₆ OCH₂CH₃ —— 0.82 (d,6H), 0.86(t,3H), 1.18 (m,2H), 1.27 (t,3H), 1.28 (m,2H), 1.30(m,2H), 1.47 (m,2H), 1.63 (m,4H), 2.96 (m,1H). 3.56 (m,2H), 4.24 (m,2H),4.44 (m,1H), 6.98 (d,2H), 7.14 (t,1H), 8.53 (d,1H), 12.67 (s,1H)*** 175.3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —(CH₂)₂CH(CH₃)₂ —COR₆ OCH₃ — —0.88 (t,3H), 0.91 (d,6H), 1.37 (m,2H), 1.52 (m,4H), 1.63 (m,2H), 3.00(m,1H), 3.63 (m,2H), 3.78 (s,3H), 4.45 (m,1H), 6.99 (d,2H), 7.10 (t,1H),8.56(d,1H), 12.67 (s,1H)*** 176. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—CH₃ —COR₆ NR₇R₈

−103° 0.92 (t,3H), 1.38 (m,2H), 1.65 (m,2H), 2.14 (s,3H), 2.88 (m,2H).2.97 (s,3H), 3.63 (s,2H), 3.67 (m,2H), 4.51 (rn,1H), 7.04 (d,2H), 7.12(t,1H), 7.24-7.30 (m,5H), 8.55 (d,1H), 12.46 (s,1H),*** 177. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —CH₃ —COR₆ NR₇R₈

−97° 0.91 (t,3H), 1.37 (m,2H), 1.67 (m,2H), 2.45 (s,3H), 2.85 (m,2H),3.45 (m,2H), 3.60 (s,2H), 4.53 (m,1H), 7.03 (d,2H), 7,14 (t,1H),7.24-7.32 (m,5H), 7.99 (d,1H), 8.55 (d,1H), 12.44 (s,1H)*** 178. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —CH₃ —COR₆ NR₇R₈ H, CH₃ — 0.91(t,3H), 1.37 (rn,2H), 1.66 (m,2H), 2.50 (s,3H), 2.75 (d,1H), 3.62(s,2H), 4.48 (m,1H), 7.01 (d,2H), 7.14 (t,1H), 7.91 (d,1H), 8.54 (d,1H),12.43 (s,1H)*** 179. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.91 (t,3N), 1.35 (m,2H), 1.72 (rn,2H), 3.60 (m,2H), 3.85(s,3H), 4.47 (m,1H), 7.02 (d,2H), 7.09 (t,1H), 7.10-7.47 (rn,9H), 8.55(d, 1H), 12.80 (s,1H)*** 180. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.93 (t,3H), 1.32 (rn,2H), 1.70 (m,2H), 3.66 (rn,2H), 3.78(s,3H), 3.50 (m,1H), 6.90-6.95 (m,3H), 7.08 (d,2H), 7.17 (t,1H), 7.29(t,1H), 8.58 (d,1H), 9,68 (s,1H), 12.77 (s,1H)*** 181. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.92 (t,3H), 1.36 (m,2H), 1.70 (rn,2H), 3.49 (s,3H), 3.61(rn,2H), 4.50 (m,1H), 7.02 (d,2H), 7.10 (t,1H), 7.53-7.62 (m,5H), 8.04(m,2H), 8.55 (d,1H), 12.87 (s,1H)*** 182. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.93 (t,3H), 1.39 (m,2H), 1.68 (m,2H), 3.57 (m,5H), 4.49(m,1H), 5.15 (s,2H), 7.06 (d,2H), 7.19 (t, 1H), 7.34 (m,5H), 8.60(s,1H), 12.67 (s,1H)*** 183. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.93 (t,3H), 1.39 (m,2H), 1.68 (m,2H), 3.61 (m, 2H), 3.73(s,3H), 4.82 (s,3H), 4.47 (m,2H), 7.06 (d, 2H), 7.04-7.14 (m,6H), 7.40(t,1H), 8.56 (s,1H), 12.72 (s,1IH)*** 184. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.91 (1,3H), 1.34 (m,2H), 1.39 (s,3H), 1.69 (m,2H), 3.57(m,2H), 3.71 (s,3H), 4.10 (m,2H), 4.47 (m, 1H), 7.07 (m,6H), 7.35(t,1H), 8.55 (s,1H), 12.78 (s, 1H)*** 185. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ OC(CH₃)₃ — — 0.89 (t,3H), 1.31 (d,6H),1.37 (m,2H), 1.55 (s,9H), 1.64 (m,2H), 3.59 (m,2H), 3,95 (m,2H), 4.45(m,1H), 7.09 (d,2H), 7.12(t,1H), 8.49 (s,1H), 12.40 (s, 1H)*** 186. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ NR₇R₈

— 0.91 (m,3H) 1.22 (m,6H), 1.32 (m,2H); 1.69 (m,2H); 2.89 and 3.01(2s,3H) ; 2.91 (m,2H); 3.07- 3.40 (m,2H); 3.70 (rn,2H); 3.71 (m,1H);4.45-4.51 (2m,1H); 7.02 (m,2H) ; 7.18 (m,2H); 7.25 (m,2H); 7.35 (m,2H);8.53 (m,1H); 12.25 (s,1H)*** 187.

CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ OCH₃ — −56° 0.96 (t,3H); 1.36 (d,6H);1.42 (m,2H); 1.87 (m,2H); 3.85 (s,3H); 4.07 (m,1H); 4.59 (m,1H); 7.38(d,1H); 8.22 (d,1H); 8.26 (d,1H); 9.22 (d,1H); 12.68 (broad s,1H)***188. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.92 (t,3H); 1.32-1.39 (m,2H); 1.75 (m,2H); 3.64 (m,2H); 3.75(s,3N); 4.48 (m,1H); 7.06 (m,4H); 7.13 (m,3H); 7.24 (m,1H); 7.49 (m,2H); 7.55 (m,2H); 8.56 (m,1H); 12.77 (s,1H)*** 189. 3,5- difluorophenyl OH,H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — −56° 0.89 (1,3H); 1.29 (m,2H); 1.79 (m,2H); 3.63 (s,3H); 4.54(m,1H); 5.13 (s,1H); 5.17 (s,2H); 6.62 (s,1H); 7.07 (t,1H); 7.23 (m,4H);7.33 (rn,6H); 7.43 (rn,1H); 8.35 (d,1H); 12.68 (s,1H)s*** 190. 3,5-difluorophenyl OH, H(R) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.94 (t,3H); 1.28-1.35 (2m,2H); 1.78 (m,2H); 3.65 (s,3H); 4.49(m,1H); 5.13 (2s,3H); 6.47 (s,1H); 7.05 (t,1H); 7.21 (m,4H); 7.35(m,6H); 7.45 (m,1H); 8.38 (d,1H); 12.70 (s,1H)*** 191. 3,5-difluorophenyl

CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.99 (t,3H); 1.47 (m,2H); 1,80-1.86 (2m,2H); 3.64 (s,3H); 4.67(m,1H); 5.19 (s,2H); 7.08 (t,1H); 7.24 (d,1H); 7.30-7.50 (m,8H); 7.78(m,2H); 9.46 (broads s 1H); 12.87 (broad s 1H)*** 192. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.98 (t,3H); 1.35-1.45 (m,2H); 1.75 (m,2H); 3.60 (m+s,5H); 3.50(m,1H); 7.06 (d,2H); 7.15 (t,1H); 7.60 (d,1H); 7.77 (m,2H); 7.90 (d,1H);8.55 (broad s 1H); 12.90 (s,1H)*** 193. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.97 (t,3H); 1.39 (m,2H); 1.75 (m,2H); 3.64 (m,2H); 3.81(s,3H); 4.11 (s,3H); 4.51 (m,1H); 7.07 (m,3H); 7.17 (m,2H); 7.38 (d,1H);7.48 (m,1H); 8.58 (broad s,1H); 12.75 (broad s 1H)*** 194. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.94 (t,3H); 1.35 (m,1H); 1.40 (m,1H); 1.71 (m,2H); 2.17(s,3H); 3.62 (m,2H); 3.73 (s3H); 4.47 (m,1H); 7,04 (d,2H); 7.15 (t,1H);7.29 (broad s 2H); 7.36 (m,2H); 8.56 (broad d 1H); 12,78 (broad s 1H)***195.

CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ OCH₃ — −28.5° 0.94 (t,3H); 1.07 (m,2H);1,19 (m,2H); 1.32 (d,6H); 1,37 (m,2H); 1.80 (m,2H); 2.86 (m,1H); 3.85(s,3H); 4.03 (m,1H); 4.50 (m,1H); 8.80 (d,1H); 12.56 (broad s 1H)***196. 3,5- difluorophenyl

CH₃(CH₂)₂— (S) —COR₆

OCH₃ — −71° 0.94 (t,3H);1.37 (m,2H); 1.79 (m,2H); 3.87 (s,3H); 4.54(s,2H); 4.58 (m,1H); 7.29 (m,1H); 7.35 (m,4H); 7.75 (m,3H); 9.38 (m,1H);12.66 (broad s 1H)*** 197. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.95 (t,3H); 1.39-1.44 (2m,2H); 1.77 (m,2H);1,38and 1.43(2m,2H); 1.75 (m,2H); 3.69 (m,2H); 3.81 (s,3H); 4,48 (m,1H); 7.15(d,2H); 7.22 (t,1H); 7.45 (m,1H); 7.51 (m,2H); 7.79 (d,1H); 8.58 (broads 1H); 12.89 (broad s 1H)*** 198. 3,5- difluorophenyl H, H CH₃(CH₂)₂—(S) —COR₆ —CH(CH₃)₂ NR₇R₈

— 0.93 (t,3H); 1.28 (d,6H); 1.38 (m,2H); 1.68 (m,2H); 2.50 (m,4H); 2.56(m,2H); 3.45 (m,2H); 3.60 (m,6H); 4.28 (m,1H); 4.52 (m,1H); 7.06 (d,2H);7.14 (t,1H); 7.73 (m,1H); 8.57 (d,1H); 12.30 (broad s 1H)*** 199. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.94 (t,3H); 1,37-1.43 (2m,2H); 1.73 (m,2H); 3.60 (m,2H); 3.74(s,3H) ; 4.50 (m,1H); 5.20 (s,2H); 7,06 (d,2H); 7.12 (m,3H); 7.36-7.50(m,7H); 8.56 (d,1H); 12.76 (broad s 1H)*** 200. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.93 (t,3H); 1.32-1,40 (m,2H); 1.70 (m,2H); 3.60 (m,2H); 3.78(s,3H) ; 4.50 (m,1H); 7.03 (d,2H) ; 7.12 (t,1H); 7.40 (m,1H); 7,50(m,2H); 7.53 (m,2H); 7.80 (m,4H); 8.58 (d,1H); 12.78 (broad s 1H)***201. (CH₃)₂CH— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.93 (t,3H); 0,96 (s,9H); 1,40 (m,2H); 1.78 (m,2H); 3.62(s,1H); 3.63 (s,3H); 4.59 (m,1H); 5.17 (s,2H); 5.65 (s,1H); 7.07 (m,1H);7.21 (m,1H); 7.35 (m,6H); 7.44 (m,1H); 7.80 (d,1H); 12.62 (broad s1H)*** 202. (CH₃)₂CH— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.78 (d,3H); 0.86 (t,3H); 0.97 (d,3H); 1,34 (m,2H); 1.78(m,2H); 2,06 (m,1H); 3.66 (s,3H); 3.80 (m,1H); 3.59 (m,1H); 5.17 (s,2H);5.54 (s,1H); 7.06 (m,1H); 7.20 (m,1H); 7.32 (m,6H); 7.42 (m,1H); 7.89(d,1H), 12.66 (broad s 1H) 203. (CH₃)₂CH—CH₂— OH, H(S) CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.94 (d,6H); 1.32 (m,2H); 1.50 (m,2H); 1.80 (m,2H); 1.87 (m,2H)3.78 (s,3H); 3.99 (m,1H); 3.62 (m,1H); 5.17 (s,2H); 5.60 (s,1H); 7.17(t,1H); 7.20 (d,1H); 7.30 (m,6H); 7.42 (m,1H); 7.95 (d,1H); 12.61 (broads 1H)*** 204. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂NR₇R₈

— 0.92 (t,3H); 1.24-1.29 (2d,6H); 1.40 (m,2H); 1.70 (m,2H); 2.86 and2.93 (2s,3H); 3.40 (m,1H); 3.60 (m,2H); 4.50 (m,1H); 4.60 (s) and 4.72(m) 2H; 7.08 (d,2H); 7.14(t,1H); 7.24 (d,1H); 7.39 (m,4H); 8.55 (d,1H);12.35 (broad s 1H)*** 205. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆—CH(CH₃)₂ NR₇R₈

— 0.92 (t,3H); 1.24 (d,6H); 1.32 and 1.41 (2m,2H); 1.68 (m,2H); 2.86 and3.04 (2s,3H) 3.07-3.18 (m,2H); 3.36 (m,1H); 3.60 (m,2H); 3.84 (m,1H);4.51 (m,1H) ; 7.03 (d,2H); 7.11 (t,1H); 7.2-7.4 (m,2H); 7,66 and 7.73(2t,1H); 8.45-8.57 (m,2H); 12.27 (broad s 1H)*** 206. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.91 (t,3H); 1.33-1.40 (2m,2H); 1.67 (m,2H); 3.61 (m,2H); 3.70(s,3H); 4.47 (m,1H); 6.93 (d,2H); 7.03 (t,3H); 7.14 (t,2H); 7.30 (t,1H);7.39 (t,2H); 7.48 (t,1H); 7.54 (t,1H); 8.54 (d,1H); 12.78 (broad s1H)*** 207. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.92 (t,3H); 1,32-1.41 (2m,2H); 1,67 (m,2H); 3.60 (s + m,5H);3.66 (s,3H); 3.88 (s,3H); 4.48 (m,1H); 6.93 (d,1H); 7.03 (d,2H); 7,17(m,3H); 8.56 (d,1H); 12.70 (broad s 1H)*** 208. 2-benzyloxy-3,5-difluorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ OCH₃ — — 0.92(t,3H); 1,31 (d,6H); 1.35 (m,2H); 1.79 (m,2H); 3.86 (s,3H); 4.03 (m,1H);4.59 (m,1H); 5.32 (d,2H); 5.32 (s,1H); 6.80 (m,1H); 7.01 (m,1H); 7.25(m,1H); 7.40 (m,5H); 12.59 (broad s 1H)*** 209. 2-hydroxy-3,5-difluorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ OCH₃ — — 0.94(t,3H); 1.33 (d,6H); 1.34 (m,2H); 1.82 (m,2H); 3.84 (s,3H); 4.04 (m,1H);4,60 (m,1H); 5.30 (m,1H); 6.71 (m,1H); 6.80- 7.20 (m,2H); 8.15 and 8.20(2d,1H); 9.76 (broad s 1H); 12.57 (broad s 1H)*** 210. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂ NR₇R₈ CH₃,—(CH₂)₂OCH₃ — 0.93 (t,3H); 1.32 (d,6H); 1.34-1.41 (2m,2H); 1.70 (m,2H);2.94 and 3.01 (2s,3H); 3.20 and 3.30 (2s,3H); 3.32-3.67 (4m,7H); 4.48(m,1H); 7.04 (d,2H); 7.13 (t,1H); 8.55 (broad s 1H); 12.28 (s, broad s1H)*** 211. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.91 (t,3H); 1,33 (m,2H); 1,67 (m,2H); 3.61 (s,3H); 3.64(m,2H); 4.43 (m,1H); 7.04 (m,2H); 7.14 (m,1H); 7.14 (m,1H); 7.22 (m,2H);7.28 (m,1H); 7.35 (m,2H); 7.48 (m,2H); 7.57 (m,1H); 8.60 (broad s 1H);12.65 (broad s 1H)*** 212. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆—CH(CH₃)₂ NR₇R₈

— 0.87 (t,3H); 1.13 (2d,6H); 1.16-1.18 (2m,2H); 1.63 (m,2H); 2,80(m,2H); 2.82 and 2.98 (2s,3H); 2.97 (m,1H); 3.15 (m,1H); 3.38 (m1H);3,60 (m,2H); 3.60-3.65-3.71 and 3.74 (4s,6H); 4,44 (m,1H); 6.58 (m,1H);6,77 (m,1H); 6.86 (m,1H); 6.97 (m,2H); 7.06 (m,1H); 8.46 (broad s 1H);12.23 (broad s 1H) 213. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.91 (t,3H); 0.93 (s,9H); 1.34 (m,2H); 1.77 (m,2H); 3.61(d,2H); 3.71 (s,3H); 4.58 (m,1H); 5.65 (d,1H); 6.93 (d,2H); 7,03 (d,1H);7.13 (t,1H); 7.29 (t,1H); 7.36 (t,2H); 7.48 (t,1H); 7.51 (d,1H); 7.86(d,1H); 12.66 (broad s 1H)*** 214. 3,5- difluorophenyl H, H CH₃(CH₂)₂—(S) —COR₆

OCH₃ — — 0.93 (t,3H); 1.35-1.40 (2m,2H); 1.70 (m,2H); 3.60 (m,2H); 3.68(s,3H); 4.50 (m,1H); 7.03 (d,2H); 7.12 (t,1H); 7.55 (m,2H); 7.63 (m,2H);8.57 (broad s 1H); 12.88 (broad s 1H)*** 215. 3,5- difluorophenyl OH,H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.85 (t,3H); 1.26-1.29 (2m,2H); 1.75 (m,2H); 3.68 (s,3H); 4.47(m,1H); 5.09 (s,1H); 6.58 (s,1H); 6.92 to 7.52 (7m,12H); 8.30 (broad s1H); 12,68 (broad s 1H)*** 216. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.91 (t,3H); 1.02 (s,9H); 1.35 (m,2H); 1.75 (m,2H); 3.58(s,3H); 3.59 (s,1H); 4.54 (m,1H); 5.66 (s,1H); 7.20-7.57 (5m,9H); 7.83(d,1H); 12.55 (broad s 1H)*** 217. 3,5- difluorophenyl OH, H CH₃(CH₂)₂—(S) —COR₆

NR₇R₈ H, H — 0.91 (t,3H); 1.29 (m,2H); 1.79 (m,2H); 4.58 (m,1H); 5.15(d,1H); 6.48 and 6.63 (2s,1H); 7.12 (m,3H); 7,42 (m,4H); 7.58 (m,1H);7.59 (s,2H); 8.34 and 8.40 (2d,1H); 12.41 (broad s 1H)*** 218. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆ —CH(CH₃)₂

— — 0.92 (t,3H); 1.25 (d,6H); 1.38 (m,2H); 3.05 (m,2H); 3.61 (m,2H);3.88 (m,1H); 4.43 (m,1H); 4.51 (m,2H); 7.04 (d,2H); 7.15 (t,1H); 7.27(m,1H); 7.36 (s,4H); 8.52 (d,1H); 12.55 (broad s 1H)*** 219. (CH₃)₂CH—OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.80 (d,3H); 0.87 (t,3H); 0.90 (d,3H); 1.27 (m,2H); 1.70(m,2H); 1.98 (m,1H); 3.65 (s,3H); 3.74 (m,1H); 5.48 (d,1H); 6.88 (d,2H);6.97 (d,1H); 7.09 (t,1H); 7,24 (t,1H); 7.20 (m,2H); 7.30 (m,1H); 7.34(d,1H); 7.85 (d,1H); 12.63 (s,1H)*** 220. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.86 (t,3H); 1.32 (m,2H); 1.63 (m,2H); 3.55 (m,2H); 3.59(s,3H); 4.43 (m,1H); 4.91 (s,2H); 6.83 (d,2H); 6.86 (m,1H); 6.99 (d,2H);7.07 (m,1H); 7.18 (m,2H); 7.37 (t,1H); 7.40 (t,1H); 7.47 (t,1H); 7.57(d,1H); 8.52 (d,1H); 12.62 (s,1H)*** 221. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂—(S) —COR₆

OCH₃ — — 0.87 (t,3H); 0.90 (s,9H); 1.28 (m,2H); 1.70 (m,2H); 3.55(s,1H); 3.59 (s,3H); 4.53 (m,1H); 4.91 (s,2H); 5.59 (d,1H); 6.83 (d,2H);6.90 (t,1H); 7.22 (m,2H); 7.34 (d,1H); 7.40 (t,1H); 7.45 (t,1H); 7.59(t,1H); 7.82 (d,1H); 12.67 (s,1H)*** 222. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂—(S) —COR₆

OCH₃ — — 0.96 (t,3N ; 0.99 (s,9H); 1.44 (m,2H); 1.77 (m,2H); 3.38(s,3H); 3.64 (s,1H); 4,64 (m,1H); 5.26 (s,2H); 5.68 (d,1H); 7.12 (t,1H);7.24 (d,1H); 7.34 (d,1H); 7.38 (m,1H); 7.44 (m,2H); 7.82 (t,1H); 7.90(d,1H); 8.62 (d,1H); 12.68 (s,1H)*** 223. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.99 (t,3H); 1.46 (m,2H); 1.77 (m,2H); 3.63 (s,3H); 3,66(m,2H); 4.54 (m,1H); 5.28 (s,2H); 7.10-7.48 (several m,9H); 7.83 (t,1H);8.63 (m,2H); 12.80 (broad s 1H)*** 224. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.85 (t,3H); 0.91 (s,9H); 1.29 (m,2H); 1.68 (m,2H); 3.53(s,3H); 3.56 (m,2H); 4,52 (m,1H); 5,24 (s,2H); 5.58 (d;1H); 7.05 (t,1H);7.13 (d,1H); 7.36 (d,1H); 7.41 (t,1H); 7.54 (d,1H); 7.62 (t,1H); 7.73(d,1H); 7.81 (d,1H); 12.55 (s,1H)*** 225. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂—(S) —COR₆

OCH₃ — — 0.87 (t,3H); 0.91 (s,9H); 1.28 (m,2H); 1.70 (m,2H); 3.56(s,2H); 3.56 (s,3H); 4.54 (m,1H); 5.15 (s,2H); 5.60 (d,1H); 7.05 (t,1H);7.20 (m,3H); 7.33 (m,3H); 7.39 (m,1H); 7.81 (d,1H); 12.54 (broad s1H)*** 226. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.96 (t,3H); 0.99 (s,9H); 1,35 (m,2H); 1.80 (m,2H); 3.64(d,1H); 3.65 (s,3H); 4,63 (m,1H); 5.23 (s,2H); 5,68 (d,1H); 7.12- 7.22(m,5H); 7.45 (m,3H); 7.92 (d,1H); 12.67 (broad s 1H)*** 227. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.87 (t,3H); 1.32 (m,2H); 1.64 (m,2H); 3.57 (s,3H); 3.60(m,2H); 4.43 (m,1H); 5.14 (s,2H); 6.98-7.40 (m,1H); 8.51 (d,1H); 12.63(broad s 1H)*** 228. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.95 (t,3H); 1.43 (m,2H); 1.71 (m,2H); 3.66 (m+s, 5H); 4.50 (m,1H); 5.18 (s,2H); 7.06-7.19 (m,8H); 7.44 (m,3H); 8.64 (d,1H); 12.72(broad s 1H)*** 229. 3,5- difluorophenyl OH, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.83 (t,3H); 1.25 (m,2H); 1,69 (m,2H); 3.55 (s,3H); 4.45(m,1H); 5.09 (m,1H); 5.16 (s,2H); 6.44 and 6.58 (2d,1H); 7.02 (t,1H);7.14 (m,4H); 7.24-7.37 (m,4H); 7.33 (m,1H); 8.30 and 8.32 (2d,1H); 8.52(s,1H); 12.63 and 12.71 (broad 2s 1H)*** 230. (CH₃)₃C— OH, H(S)CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.97 (t,3H); 1.02 (s,9H); 1.36 (m,2H); 1.80 (m,2H); 2.30(s,3H); 3.65 (s,3H); 3.67 (m,2H); 4.65 (m.1H); 5.18 (s,2H); 5,70 (d,1H);7.10-7.50 (5m,8H); 7.96 (d,1H); 12.68 (broad s 1H)*** 231. 3,5-difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.96 (t,3H); 1.39 (m,2H); 1.71 (m,2H); 2.36 (s,3H); 3.60(s,3H); 3.62 (m,2H); 4.50 (m,1H); 5,16 (s,2H); 7,06-7.48 (6m,11H); 8.67(d,1H); 12.77 (s,1H)*** 232. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.95 (t,3H); 0.99 (s,9H); 1.37 (m,2H); 1.81 (m,2H); 3.64(m,2H); 3.67 (s.3H); 4.63 (m,1H); 5.22 (s,2H); 5.71 (d,1H); 7.10 (t,1H);7.22 (d,1H); 7.33 (d,1H); 7.40-7.50 (m,5H); 7,94 (d,1H); 12,62 (broad s1H)*** 233. CF₃ OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.96 (t,3H); 1,37 (m.2H); 1,82 (m,2H); 3.66 (s,3H); 4.60(m,1H); 4.72 (m,1H); 5.23 (s,2H); 7.01-7.50 (2m,8H); 8.62 (d,1H); 12.86(broad s 1H)*** 234. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) CH₃ —COR₆NR₇R₈ CH₃, CH₃ — 0.96 (t,3H); 1.40 (m,2H); 1,72 (m,2H); 2.32 (s,3H);3.06 (s,6H); 3.62 (m,2H); 4.52 (m,1H); 7,08 (d,2H); 7.16 (t,1H); 8.58(d,1H); 12.42 (broad s 1H)*** 235. 3,5- difluorophenyl H, H CH₃(CH₂)₂—(S) CH₃ —COR₆ NR₇R₈

— 0.85 (t,3H); 1.27 (m,2H); 1.62 (m,2H); 2.41 (s,3H); 2.78 (t,2H); 3.37(t,2H); 3,55 (m,2H); 3.78 (s,3H); 4.43 (m,1H); 6.87 (t,1H); 7.08 (m,3H);7.11 (m,2H); 7.20 (t,1H); 7.95 (broad s 1H); 8.51 (d,1H); 12.38 (broad s1H) 236. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) H —COR₆ OCH₃ — — 0.93(t,3H); 1.30 and 1.41 (2m,2H); 1.70 (m,2H); 3.61 (m,2H); 3.85 (s,3H);4.53 (m,1H); 7.04 (d,2H); 7.17 (t,1H); 8,21 (s,1H); 8.63 (d,1H); 12.82(broad s 1H)*** 237. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) H —COR₆ NR₇R₈

— 0.91 (t,3H); 0.95 (s,9H); 1.32 and 1.35 (2m,2H); 1.74 (m,2H); 2.90(m,2H); 3.18 (broad s 3H); 3.60 (d,1H); 3.71 (m,2H); 3.61 (m,1H); 5.63(d,1H); 7.22-7.35 (m,5H); 7.90 (d,1H); 12.49 (broad s 1H)*** 238.(CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.96 (t,3H); 1.14 (s,9H); 1.39 (m,2H); 1.82 (m,2H); 3.65(s,3H); 3.67 (s,1H); 4.64 (m,1H); 5.27 (s,2H); 5.73(d,1H); 7.16 (m,1H);7.28 (d,1H); 7.40-7.50(4m,6H); 8.01 (d,1H); 12.70 (s, broad 1H)*** 239.(CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.94 (t,3H); 0.97 (s,3H); 1,34 (m,2H); 3.62 (s,3H); 3.63(s,1H); 5.87 (m,2H); 5.15 (s,2H); 7.15 (m,3H); 7.41 (d,2H); 7.50 (m,2H);7.69 (d,1H); 12.67 (s broad 1H)*** 240. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S)—COR₆

OCH₃ — — 0.97 (t,2H); 0.99 (s,9H); 1.39 (m,2H); 1.80 (m,2H); 3.65(s,3H); 3.66 (s,1H); 4.63 (m,1H); 5.24 (s,2H); 5.70 (d,1H); 7,05- 7.27(3m,5H); 7.45-7.49 (2m,2H); 7.93 (d,1H); 12.70 (s broad 1H)*** 241.(CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.87 (t,3H); 0.91 (s,9H); 1.30 (m,2H); 1.73 (m,2H); 3.56(2s,4H); 4.54 (m,1H); 5.19 (s,2H); 5.60 (d,1H); 7.06 (m,1H); 7.16(m,2H); 7.23 (d,1H); 7.32-7.41 (m,3H); 7.82 (d,1H); 12.70 (s broad1H)*** 242. (CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.87 (t,3H); 0.91 (s,9H); 1.27 (m,2H); 1.45 (m,3H); 1.69(m,1H); 2.32 (m,1H); 3.13 (m,1H); 3.56 (d,1H); 3.70 (s,3H); 4.52 (m,1H);5.57 (d,1H); 7.19 (m,3H); 7.29 (m,2H); 7.80 (d,1H); 12.47 (s broad1H)*** 243. 3,5- difluorophenyl H, H CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.95 (t,3H); 1.35-1.41 (m,2H); 1.51 (M,1H); 1.72 (m,3H); 2.38(m,1H); 3.20 (m,1H); 3.63 (m,2H); 3.76 (s,3H); 7.26 (m,3H); 7.33 (m,2H);8.54 (s broad 1H); 12.65 (s broad 1H)*** 244. 3,5- difluorophenyl H, HCH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.94 (t,3H); 1.39 (m,2H); 1.70 (m,2H); 3.62 (m+s.5H); 4.48(m,1H); 4.91 (s,2H); 7.04 (d,2H); 7.12 (m,3H); 7.22 (m,5H); 7.40 (m,1H);8.57 (d broad 1H); 12.77(s broad 1H)*** 245. (CH₃)₃C— OH, H(S)CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.96 (t,3H); 0.98 (s,9H); 1.39 (m,2H); 1.80 (rn,2H); 3.65(m,1H); 3.66 (s,3H); 4.64 (m,1H); 4.95 (s,2H); 5.65 (s,1H); 7.15 (m,2H);7.27 (m,5H); 7.45 (m,1H); 7.91 (d,1H); 12.70 (s broad 1H)*** 246.(CH₃)₃C— OH, H(S) CH₃(CH₂)₂— (S) —COR₆

OCH₃ — — 0.95 (t,3H); 0.98 (s,9H); 1.37 (m,2H); 1.80 (m,2H); 3.63(d+s,5H); 4.61 (m,1H); 5.22 (s,2H); 5.68 (d,1H); 7.12 (t,1H); 7.16(m,1H); 7.29 (m,3H); 7.40 (d,1H); 7.50 (m,1H); 7.89 (d,1H); 12.65 (sbroad 1H)*** 247. 3,5- difluorophenyl OH, H CH₃(CH₂)₂— (S) H —COR₆ NR₇R₈CH₃,

— 082 (t,3H); 1.16-1.28 (m,2H); 1.67 (m,2H); 2.86 (s broad 2H); 3.29(sbroad 3H); 3.66 (s broad2H); 4.52(m,1H); 5.08 (2d,1H); 6.40 et 6.55(2d,1H); 7.09-7.28 (3m,8H); 7.60 (sbroad 1H); 8.27 et 8.34 (2d,1H);12.44 (s broad1H)**** In the table (S) or (R) in the columns “R₃” and“R₂, R′₂” indicate the stereochemistry of the asymmetric carbon, bearingR₃or R′₂in the formula (I). However, it is understood that, theindication (S) or (R) does not relate to the case in which R₂andR′₂taken together form an oxo group.In the table (S) or (R) in the columns “R₃” and “R₂, R′₂” indicate thestereochemistry of the asymmetric carbon, bearing R₃ or R′₂ in theformula (I). However, it is understood that, the indication (S) or (R)does not relate to the case in which R₂ and R′₂ taken together form anoxo group.

The compounds of the invention were subjected to pharmacological testswhich showed their advantage as active substances in therapy.

They were tested in particular for their inhibitory effects on theproduction of β-amyloid peptide (β-A4).

β-Amyloid peptide (β-A4) is a fragment of a larger precursor proteincalled APP (amyloid precursor protein). The latter is produced and ispresent in various cells of human or animal tissue. However its cleavagein cerebral tissue by protease-type enzymes leads to the formation ofthe β-A4 peptide, which accumulates in the form of an amyloid plaque.The two proteases responsible for producing the amyloid peptide areknown by the name of beta- and gamma-secretases (Wolfe M S, Secretasetargets for Alzheimer's disease: identification and therapeuticpotential, J Med. Chem. 2001 Jun. 21; 44 (13): 2039-60).

It has however been demonstrated that this gradual deposition of theβ-A4 peptide is neurotoxic and might play an important role inAlzheimer's disease.

Accordingly, the compounds of the present invention, as an inhibitor ofthe production of the β-amyloid peptide (β-A4) by inhibition ofgamma-protease, can be used in the treatment of pathologies such assenile dementia, Alzheimer's disease, Down's syndrome, Parkinson'sdisease, amyloid angiopathy and/or cerebrovascular disorders.

The tests were conducted in accordance with the protocol describedbelow.

For the β amyloid cellular test, the CHO—K1 line coexpressing the CT100of APP and PS1 M146L clone 30-12 is used. The line targets theinhibition of gamma-secretase. Presenilin is linked to gamma-secretaseactivity (Wolfe M S, Haass C., The Role of presenilins ingamma-secretase activity, J Biol Chem. 2001 Feb. 23; 276(8): 5413-6) andits coexpression with the amyloid protein or its N-terminal fragmentcauses an increase in secretion of the peptide A1-42 (β-A4), therebygenerating a pharmacological tool which allows inhibition by thecompounds of formula (I) of the production of the β-A4 peptide to beevaluated. 96-well culture plates are inoculated with 1×10⁵ cells perwell in 150 μl of incubation medium. The presence of a minimumpercentage (1.3% final) of serum allows cellular adhesion to the plasticafter 2.3 hours of incubation at 37° C., in the presence of 5% CO₂. Theproducts (15 μl) are tested at 10 μM DMSO 1% final and are incubated for24-25 h at 37° C. in the presence of 5% CO₂ and 100% humidity. Afterthis 24-25 h incubation, the cellular supernatants (100 μl) aretransferred to ELISA plates, treated with the capture antibody 6E10(6E10, epitope: aal-17, INTERCHIM/SENETEK 320/10, to determine theamount of amyloid peptides secreted by the cells in the presence ofcompounds according to the invention. A series of synthetic controlpeptide, “peptide 1-40”, at 5 and 10 ng/ml is treated in parallel. TheELISA plates are incubated overnight at 4° C.

The quantity of bound peptide is detected indirectly in the presence ofa competitor which corresponds to the truncated peptide, peptide 1-28coupled to biotin, which is then detected with streptavidin coupled toalkaline phosphatase. The substrate, p-Nitrophenyl Phosphate (pNPP FASTp-nitrophenyl phosphate, Sigma N2770), gives a yellow, soluble reactionproduct which can be read at 405 nm. The reaction is stopped with 0.1MEDTA solution. For this purpose, following binding the amyloid peptidein the ELISA plate, 50 μl of biotinylated peptide 1-28 are added to 100μl of cellular supernatant and incubated for 30 minutes at ambienttemperature. The ELISA plates are then washed 3 times. After drying byinversion on absorbent paper, 100 μl of streptavidin-alkalinephosphatase (Interchim/Jackson ImmunoResearch Laboratories 016-050-084)are added per well and incubated for 1 hour at ambient temperature. Theplates are washed again and then the alkaline phosphatase substrate(pNPP 1 mg/ml) is added in an amount of 100 μl per well. After 30minutes of incubation at ambient temperature the reaction is stopped byadding 100 μl per well of 0.1M EDTA and reading is carried out 405 nm.

The compounds of formula (I) according to the present invention showedan IC50 (50% inhibitory concentration) of less than 500 nM, moreparticularly less than 100 nM.

The results of biological tests show that the compounds are inhibitorsof the formation of the β-amyloid peptide (β-A4).

Accordingly these compounds can be employed in the treatment ofpathologies in which a β-amyloid peptide (β-A4) formation inhibitorprovides a therapeutic benefit. In particular, such pathologies includebut not limited to senile dementia, Alzheimer's disease, Down'ssyndrome, Parkinson's disease, amyloid angiopathy and cerebrovasculardisorders.

The use of the compounds according to the invention for preparing amedicament intended for treating the abovementioned pathologies forms anintegral part of the invention.

The invention further provides medicaments which comprise a compound offormula (I), or an addition salt thereof with a pharmaceuticallyacceptable acid or a hydrate or a solvate of the compound of formula(I). These medicaments find their use in therapy, in particular, in thetreatment of the abovementioned pathologies.

Another aspect of the present invention relates to pharmaceuticalcompositions comprising as active principle at least one compoundaccording to the invention. These pharmaceutical compositions comprisean effective dose of a compound according to the invention, or of apharmaceutically acceptable salt, hydrate or solvate of the saidcompound, and, optionally, one or more pharmaceutically acceptableexcipients.

The said excipients are selected, according to the pharmaceutical formand the desired mode of administration, from the customary excipientswhich are known to the person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration theactive principle of formula (I) above, or where appropriate its salt,solvate or its hydrate can be administered in unit form foradministration, as a mixture with conventional pharmaceuticalexcipients, to animals and to human beings for the prophylaxis ortreatment of the above diseases or disorders.

The appropriate unit forms for administration embrace the forms for oraladministration such as tablets, soft or hard gelatin capsules, powders,granules, chewing gums and oral solutions or suspensions, the forms forsublingual, buccal, intratracheal, intraocular or intranasaladministration or for administration by inhalation, the forms forsubcutaneous, intramuscular or intravenous administration and the formsfor rectal or vaginal administration. For topical application thecompounds according to the invention can be used in creams, ointments orlotions.

By way of example, a unit for administration of a compound according tothe invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mgCroscaramellose sodium 6.0 mg Corn starch 15.0 mgHydroxypropyl-methylcellulose 2.25 mg Magnesium stearate 3.0 mg

In order to obtain the desired therapeutic or prophylactic effect, thedose of active principle may vary between 0.1 mg and 200 mg per kg ofbody weight per day. Although these dosages are average-situationexamples, there may be particular cases in which higher or lower dosagesare appropriate: such dosages are likewise part of the invention. Inaccordance with customary practice, the dosage appropriate to eachpatient is determined by the doctor in accordance with the mode ofadministration, the weight and the response of the said patient.

Each unit dose can contain from about 0.1 to about 1000 mg, preferablyfrom about 0.1 to about 500 mg, of active principle in combination withone or more pharmaceutical excipients. This unit dose can beadministered from 1 to 5 times per day in order to administer a dailydose of from about 0.5 to about 5000 mg, preferably from about 0.5 toabout 2500 mg.

There may be particular cases in which higher or lower dosages areappropriate; such dosages are not outside the scope of the invention. Inaccordance with customary practice, the dosage appropriate to eachpatient is determined by the doctor in accordance with the mode ofadministration, the weight and the response of the said patient.

In another of its aspects the present invention likewise relates to amethod of treating the pathologies indicated above which comprisesadministering a compound according to the invention, a pharmaceuticallyacceptable salt or a hydrate of the said compound.

1. A method of treating senile dementia, comprising administering to apatient in need of said treatment a compound of formula (I), includingin the form of a pharmaceutically acceptable base or salt:

wherein R₁ is: C₁₋₆ alkyl optionally substituted by one or twosubstituents selected from hydroxyl, trifluoromethyl, C₁₋₆ alkoxy, C₁₋₆thioalkyl, thiophene or phenyl; or C₃₋₇ cycloalkyl, thiophene,benzothiophene, pyridinyl, furanyl or phenyl; said phenyl beingoptionally substituted by one to three substituents selected fromhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyl, methylenedioxy, phenoxy orbenzyloxy; R₂ and R′₂ are independently of one another selected from:hydrogen, halogen, hydroxyl, C₁₋₃ alkoxy, C₁₋₃ alkyl, C₃₋₇ cycloalkyl,or O—C(O)—C₁₋₆ alkyl; or R₂ and R′₂ taken together form an oxo group; R₃is: hydrogen or C₁₋₆ alkyl optionally substituted by hydroxyl or C₁₋₃alkoxy; R₄ and R₅ are independently of one another selected from:hydrogen, C₁₋₇ alkyl optionally substituted by C₃₋₇ cycloalkyl orphenyl; or C₃₋₇ cycloalkyl, phenyl, naphthyl or —C(X)R₆; said C₃₋₇cycloalkyl and phenyl being optionally substituted by one or more groupsselected from halogen, hydroxyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, phenyl,phenoxy or benzyloxy; provided that at least one of R₄ or R₅ is —C(X)R₆; wherein X is oxygen or sulfur; R₆ is C₁₋₆ alkoxy, hydroxyl or—NR₇R₈; and wherein R₇ and R₈ are independently of one another selectedfrom: hydrogen, C₁₋₆ alkyl optionally substituted by C₃₋₇ cycloalkyl,C₃₋₇ cycloalkenyl, phenyl or pyridinyl; or C₃₋₇ cycloalkyl, C₁₋₆ alkoxyor phenyl; said C₃₋₇ cycloalkyl and phenyl being optionally substitutedby C₁₋₃ alkyl, hydroxyl, C₁₋₃ alkoxy or halogen; or R₇ and R₈ takentogether with the nitrogen atom to which they are attached formaziridine, azetidine, pyrrolidine, piperidine or morpholine.
 2. Themethod as set forth in claim 1, wherein in the compound of formula (I)R₁ is: C₁₋₅ alkyl, optionally substituted by one or two substituentsselected from hydroxyl, C₁₋₄ thioalkyl, thiophene or phenyl; or C₄₋₇cycloalkyl, furanyl, thiophene, benzothiophene, pyridinyl or phenyl;said phenyl being optionally substituted by one or two substituentsselected from halogen, hydroxyl, benzyloxy or methylenedioxy; R₂ and R′₂are independently of one another selected from: hydrogen, halogen,hydroxyl, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, O—C(O—C₁₋₄ alkyl; orR₂ and R′₂ taken together form an oxo group; R₃ is: C₁₋₄ alkyl,optionally substituted by C₁₋₃ alkoxy; R₄ and R₅ are independently ofone another selected from: hydrogen, C₁₋₇ alkyl, optionally substitutedby phenyl or C₃₋₇ cycloalkyl; or C₃₋₇ cycloalkyl, phenyl, naphthyl or—C(X) R₆; said phenyl being optionally substituted by one or two groupsselected from C₁₋₃ alkyl, hydroxyl, C₁₋₃ alkoxy, phenoxy or benzyloxy;provided that at least one of R₄ or R₅ is —C(X) R₆; wherein X is oxygen;R₆ is C₁₋₆ alkoxy, hydroxyl or —NR₇R₈; R₇ and R₈ are independently ofone another selected from: hydrogen, C₁₋₃ alkyl, optionally substitutedby C₃₋₇ cycloalkenyl, phenyl or pyridinyl; or C₁₋₃ alkoxy or C₃₋₆cycloalkyl; or R₇ and R₈ taken together with the nitrogen atom to whichthey are attached form azetidine, piperidine or morpholine.
 3. Themethod as set forth in claim 1, wherein in the compound of formula (I)R₁ is: C₁₋₆ alkyl optionally substituted by one or two substituentsselected from hydroxyl, C₁₋₆ alkoxy, C₁₋₆ thioalkyl, trifluoromethyl,thiophene or phenyl; or C₃₋₇ cycloalkyl, thiophene, benzothiophene,pyridinyl, furanyl or phenyl; said phenyl being optionally substitutedby one to three substituents selected from halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, hydroxyl, methylenedioxy, phenoxy or benzyloxy; R₂ and R′₂ areindependently of one another selected from: hydrogen, halogen, hydroxyl,C₁₋₃ alkoxy, C₁₋₃ alkyl, C₃₋₇ cycloalkyl, O—C(O)—C₁₋₆ alkyl; or R₂ andR′₂ taken together form an oxo group; R₃ is: hydrogen or C₁₋₆ alkyloptionally substituted by hydroxyl or C₁₋₃ alkoxy; R₄ and R₅ areindependently of one another selected from: hydrogen, C₁₋₇ alkyloptionally substituted by C₃₋₇ cycloalkyl or phenyl; or C₃₋₇ cycloalkyl,phenyl, naphthyl or —C(X)R₆; said C₃₋₇ cycloalkyl and phenyl beingoptionally substituted by one or more groups selected from halogen,hydroxyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, phenyl, phenoxy or benzyloxy;provided that at least one of R₄ or R₅ is —C(X)R₆; wherein X is oxygenor sulfur; R₆ is C₁₋₆ alkoxy, hydroxyl or —NR₇R₈; and wherein R₇ and R₈are independently of one another selected from: hydrogen, C₁₋₆ alkyloptionally substituted by C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, phenyl orpyridinyl; or C₃₋₇ cycloalkyl, C₁₋₆ alkoxy or phenyl; said C₃₋₇cycloalkyl and phenyl being optionally substituted by C₁₋₃ alkyl,hydroxyl, C₁₋₃ alkoxy or halogen; or R₇ and R₈ taken together with thenitrogen atom to which they are attached form aziridine, azetidine,pyrrolidine, piperidine or morpholine.
 4. The method as set forth inclaim 1, wherein in the compound of formula (I) R₁ is C₁₋₄ alkyl orphenyl substituted by two fluorine atoms; R₂ is hydroxyl and R′₂ ishydrogen; R₃ is C₁₋₄ alkyl; and X is oxygen.
 5. The method as set forthin claim 2, wherein in the compound of formula (I) R₁ is C₁₋₄ alkyl orphenyl substituted by two fluorine atoms; R₂ is hydroxyl and R′₂ ishydrogen; R₃ is C₁₋₄ alkyl; and X is oxygen.
 6. The method as set forthin claim 3, wherein in the compound of formula (I) R₁ is C₁₋₄ alkyl orphenyl substituted by two fluorine atoms; R₂ is hydroxyl and R′₂ ishydrogen; R₃ is C₁₋₄ alkyl; and X is oxygen.